Reduction Of Bonds Research Articles

Factors Governing Oxygen Vacancy Formation in Oxide Perovskites

The control of oxygen vacancy (VO) formation is critical to advancing multiple metal-oxide-perovskite-based technologies. We report the construction of a compact linear model for the neutral VO formation energy in ABO3 perovskites that reproduces, with reasonable fidelity, Hubbard-U-corrected density functional theory calculations based on the state-of-the-art, strongly constrained and appropriately normed exchange-correlation functional. We obtain a mean absolute error of 0.45 eV for perovskites stable at 298 K, an accuracy that holds across a large, electronically diverse set of ABO3 perovskites. Our model considers perovskites containing alkaline-earth metals (Ca, Sr, and Ba) and lanthanides (La and Ce) on the A-site and 3d transition metals (Ti, V, Cr, Mn, Fe, Co, and Ni) on the B-site in six different crystal systems (cubic, tetragonal, orthorhombic, hexagonal, rhombohedral, and monoclinic) common to perovskites. Physically intuitive metrics easily extracted from existing experimental thermochemical data or via inexpensive quantum mechanical calculations, including crystal bond dissociation energies and (solid phase) reduction potentials, are key components of the model. Beyond validation of the model against known experimental trends in materials used in solid oxide fuel cells, the model yields new candidate perovskites not contained in our training data set, such as (Bi,Y)(Fe,Co)O3, which we predict may have favorable thermochemical water-splitting properties. The confluence of sufficient accuracy, efficiency, and interpretability afforded by our model not only facilitates high-throughput computational screening for any application that requires the precise control of VO concentrations but also provides a clear picture of the dominant physics governing VO formation in metal-oxide perovskites.

Chemo-Enzymatic Cascade for the Generation of Fragrance Aldehydes

In this study, we present the synthesis of chiral fragrance aldehydes, which was tackled by a combination of chemo-catalysis and a multi-enzymatic in vivo cascade reaction and the development of a highly versatile high-throughput assay for the enzymatic reduction of carboxylic acids. We investigated a biocompatible metal-catalyzed synthesis for the preparation of α or β substituted cinnamic acid derivatives which were fed directly into the biocatalytic system. Subsequently, the target molecules were synthesized by an enzymatic cascade consisting of a carboxylate reduction, followed by the selective C-C double bond reduction catalyzed by appropriate enoate reductases. We investigated a biocompatible oxidative Heck protocol and combined it with cells expressing a carboxylic acid reductase from Neurospora crassa (NcCAR) and an ene reductase from Saccharomyces pastorianus for the production fragrance aldehydes.

Hydrogenation of poly(myrcene) and poly(farnesene) using diimide reduction at ambient pressure

AbstractAmbient pressure chemical hydrogenation using p‐toluene sulfonyl hydrazide (TSH) via thermal diimide formation (N2H2) permitted reduction of double bonds of poly(myrcene) (poly[Myr]) and poly(farnesene) (poly[Far]). Both pendent and backbone double bonds in poly(Myr) (Mn = 56 kg/mol) and poly(Far) (Mn = 62 kg/mol) synthesized by conventional free radical polymerization were hydrogenated to almost completion. Furthermore, TSH semi‐batch addition efficiently hydrogenated double bonds, while avoiding undesired autohydrogenation of diimides that occurred in batch mode. Thermal stability improved for hydrogenated poly(Myr) and poly(Far), where temperature at 10% weight loss (T10%) increased from 188 to 404°C for poly(Myr) and from 310 to 379°C for poly(Far). Tgs of poly(Myr) and poly(Far) also increased by about 10–25°C, indicating increased stiffness after hydrogenation. Finally, viscosities of poly(Myr) and poly(Far) were also increased after hydrogenation, and a greater increase was observed for poly(Myr) (by two orders of magnitude from 102 to 104 Pa s) due to its Mn being much higher than its entanglement molecular weight. Poly(Far) viscosity only increased by 1.5 times after hydrogenation (~104 Pa s), comparable to the poly(Myr) after hydrogenation, suggesting unsaturated poly(Far) was more entangled than unsaturated poly(Myr) because of its longer side chains.

Direct C−H Radical Alkylation of 1,4‐Quinones

Abstract1,4‐Quinones display unique redox and biological properties and have multiple applications in a wide array of fields, including health. Synthesis of diversely substituted quinone‐based compounds remains difficult and usually consists of multiple step sequences. Interest in direct C−H radical alkylation of 1,4‐quinones has thus continuously grown over this last decade. These reactions involve addition of carbon‐centered radicals generated from radical precursors through decarboxylative alkylation, hydrogen‐atom abstraction, or by carbon‐halogen bond reduction. Recent progresses in radical chemistry, including photoredox catalysis, have provided useful tools for quinone functionalization. This Minireview describes the recent progress with these methodologies, including the new promising three‐component cascade reactions involving quinones and alkenes, allowing for the preparation of complex substituted 1,4‐quinones in a single step.

Effects of N-Acetylcysteine Infusion in Patients with Sickle Cell Disease during Vaso-Occlusive Crises

Background: Our earlier studies showed that patients with sickle cell disease (SCD) have a high von Willebrand factor (VWF) activity index, which correlates with the extent of the hemolysis they experience [Chen et al Blood 2011; 117:3680‐3]. We are evaluating whether N-acetylcysteine (NAC), which dissociates VWF multimers, has a therapeutic role in SCD. Previously, we studied stable outpatients with SCD [Özpolat et al Blood Dec 2016, 128 (22) 1299]. In that study, we found that NAC infusion was safe and decreased red blood cell (RBC) fragments, dense cells, the size of VWF multimers, platelet activation, and the percentage of platelet-monocyte complexes. In addition, NAC infusion increased the total and free-thiol concentrations of cysteine and glutathione in blood, relieving oxidative stress in the patients at disease baseline. Given these findings, we have begun a pilot study of NAC in SCD patients admitted as inpatients with vaso-occlusive crisis (VOC) (NCT01800526) to examine the safety of NAC infusion and its effects on laboratory markers in that setting.Protocol and patients: Patients are approached for the study in the outpatient setting and consent is re-affirmed when they are admitted in VOC. We plan to enroll enough patients to treat 20 VOCs with NAC infusion, with each patient being treated up to two times in the study. Inclusion criteria: SCD patients with history of VOC requiring narcotics treatment. Exclusion criteria: SCD patients on chronic RBC exchange, expected to be treated by simple or exchange transfusion, inpatient with VOC in the previous 30 days, already had NAC infusion twice in our trial during VOC, and/or had oral NAC in the past 7 days. NAC (75 mg/kg/hr) is infused over 1 hr every 6 hr, for a total daily dose of 300 mg/kg. All patients also receive standard care. Blood is collected immediately before NAC infusion on the first day of admission, daily during admission, and at medical follow-ups during the first week after discharge. To date, we have completed NAC infusion in two patients with VOC under this protocol. Patient 1 is a 26-year-old male with Sβ0 thalassemia, a history of recurrent VOC and avascular necrosis (AVN) of both hips and the left shoulder, on hydroxyurea and oral narcotics. Patient 2 is a 58-year-old female with SS genotype, recurrent VOC and history of bilateral AVN of the hips and knees, pulmonary embolism, on hydroxyurea, oral narcotics, and rivaroxaban. We analyzed patient samples for dense cells, sickle cells (by imaging flow cytometry), VWF antigen and multimer distribution, ADAMTS13 activity and antigen. In addition, we will analyze the concentrations of NAC, cysteine and glutathione and their oxidized and mixed disulfide forms by mass spectrometry.Results: NAC infusions in the two SCD patients with VOC were safe and well tolerated. After NAC treatment, the number of dense cells were reduced (before vs after NAC treatment: patient 1; 1826/µl vs 46/µl, patient 2: 667/µl vs 36/µl), The VWF multimers migrated slightly faster during NAC infusion, indicating possible reduction of intra-chain disulfide bonds by NAC within VWF monomers [Chen J et al. JCI 2011, 121: 593]. The VWF concentrations were increased at the end of both NAC treatments. For patient 1, the ADAMTS13 activity was decreased during the NAC treatment, but the antigen remained unchanged. For patient 2, both the ADAMTS13 activity and antigen were increased with NAC treatment. For patient 1, phosphatidylserine positive microparticles (MP) and MP generated from RBCs and platelets were decreased with NAC treatment but there was no apparent trend for patient 2.Summary: In the first two SCD patients treated, NAC infusion during VOC was safe and well tolerated. NAC infusion decreased dense cells, and reduced intra-chain disulfide bonds in VWF. The full study should determine if NAC is useful therapy for SCD patients during VOC, acting through diverse mechanisms by improving RBC parameters and reducing adhesive activity of VWF. DisclosuresNo relevant conflicts of interest to declare.

Low-Cost Single Chamber MFC Integrated With Novel Lignin-Based Carbon Fiber Felt Bioanode for Treatment of Recalcitrant Azo Dye

A flow through anaerobic microbial fuel cell (MFC) was designed and optimized for efficient treatment of recalcitrant textile wastewater. The membrane-less MFC was first time fabricated with a unique combination of electrodes, a novel bioanode of synthesized lignin-based electrospun carbon fiber supporting a biofilm ofGeobacter sulfurreducensfor acetate oxidation and an air-breathing cathode, consisting of a pyrolyzed macrocycle catalyst mixture on carbon bonded by polytetrafluoroethylene (PTFE). The effects of different organic loadings of acetate along with Acid Orange (AO5), operation time and ionic strength of auxiliary salts (conductivity enhancers) were investigated and responses in terms of polarization and degradation were studied. In addition, the decomposition of the organic species and the degradation of AO5 along with its metabolites and degraded products (2-aminobenzenesulfonic acid) were determined by chemical oxygen demand (COD) analysis, UV-Vis spectrophotometry and high-performance liquid chromatography (UV-HPLC) techniques. SEM and TEM images were also used to find out the biocompatibility of the microbes on lignin-based electrospun carbon felt anode and the morphology of the cathode. Reduction and breakage of the azo bond of AO5 occurs presumably as a side reaction, resulting in the formation of 2-aminobenzenesulfonic acid and unidentified aromatic amines. Maximum current density of anode 0.59 Am−2and power density of 0.12 Wm−2were obtained under optimized conditions. As a result, decolouration of AO5 and chemical oxygen demand (COD) removal efficiency was 81 and 58%, respectively. These results revealed that the low-cost MFC assembly can offer significant potential for anaerobic decolouration of recalcitrant textile wastewater.

Recent developments in the reduction of unsaturated bonds by magnesium precursors

AbstractScientists have witnessed significant breakthroughs ins‐block metal chemistry. Over the past few years, several applications in catalysis associated with alkaline‐earth metal catalysts have been established owing to their abundance and lower cost. These catalysts have proved to be essential alternatives to transition metal catalysts. Several research groups have recognized the importance of magnesium complexes as highly active metal catalysts in the reduction of a series of unsaturated substrates for the synthesis of ubiquitous compounds necessary for industrial purposes. This minireview presents, based on studies published in the past recent years, a detailed discussion of catalytic hydroelementation on C–X (X = C, N, O, B, Si, S) multiple bonds, promoted by novel magnesium metal catalysts.

(Cyclopentadienone)iron Complexes: Synthesis, Mechanism and Applications in Organic Synthesis.

(Cyclopentadienone)iron tricarbonyl complexes are catalytically active, inexpensive, easily accessible and air-stable that are extensively studied as an active pre-catalyst in homogeneous catalysis. Its versatile catalytic activity arises exclusively due to the presence of a non-innocent ligand, which can trigger its unique redox properties effectively. These complexes have been employed widely in (transfer)hydrogenation (e. g., reduction of polar multiple bonds, Oppenauer-type oxidation of alcohols), C-C and C-N bond formation (e. g., reductive aminations, α-alkylation of ketones) and other synthetic transformations. In this review, we discuss the remarkable advancement of its various synthetic applications along with synthesis and mechanistic studies, until February 2021.

Antibody disulfide bond reduction and recovery during biopharmaceutical process development-A review.

Antibody disulfide bond reduction has been a challenging issue in monoclonal antibody manufacturing. It could lead to a decrease of product purity and failure to meet the targeted product profile and/or specifications. More importantly, disulfide bond reduction could also impact drug safety and efficacy. Scientists across the industry have been examining the root causes and developing mitigation strategies to address the challenge. In recent years, with the development of high titer mammalian cell culture processes to meet the rapidly growing demand for antibody biopharmaceuticals, disulfide bond reduction has been observed more frequently. Thus, it is necessary to continue evolving the disulfide reduction mitigation strategies and developing novel approaches to maintain high product quality. Additionally, in recent years as more complex molecules (such as bispecific and trispecific antibodies) emerge, the molecular heterogeneity due to incomplete formation of the interchain disulfide bonds becomes a more imperative challenging issue. Given the disulfide reduction challenges that biotech industry is facing, in this review, we provide a comprehensive scientific summary of the root cause analysis of disulfide reduction during process development of antibody therapeutics, mitigation strategies and its potential remediated recovery based on published papers. First, this paper intends to highlight different aspects of the root cause for disulfide reduction. Secondly, to provide a broader understanding of the disulfide bond reduction in downstream process, this paper discusses disulfide bond reduction impact on product stability, associated analytical methods for disulfide bond reduction detection and characterization, process control strategies as well as their manufacturing implementation. In addition, brief perspectives on the development of future mitigation strategies are also reviewed, including platform alignment, mitigation strategy application for the emerging new modalities such as bispecific and trispecific antibodies as well as using machine learning to identify molecule susceptibility of disulfide bond reduction. The data in this review are originated from the published papers.

Local Solvation Modulates Activity of Covalent C−F Bonds in Fluorinated Electrolyte Additives

Fluorinated reactants that enable fluoride bond cleavage, either in electrolytes or cathodes, are receiving increased research attention because of the formation of highly stable decomposition products (e.g. LiF), which also allows large Gibbs free energy change. Electrolytes using fluorinated solvents or additives (e.g. fluoroethylene carbonate (FEC), methyl 2,2,2-trifluoroethyl carbonate (FEMC), and liquefied CH3F) were shown to be able to effectively increase Li cyclability by forming LiF rich solid electrolyte interphase (SEI) on Li. In addition, conversion type Li battery cathodes, such as transition-metal fluorides (MFy, M=Fe, Co, Ni, Cu, y=2, 3) and CFx, can deliver high energy densities through fluoride bond reduction reactions. However, the strong electronegativity of fluorine making most of the fluoride bonds highly stable (i.e. hard to break), which limits their applications in electrochemical systems. Therefore, fundamental understanding of how to modulate fluoride bond strength to unlock activity is of vital importance. Herein, we use perfluoroalkyl group (RF)-containing liquid reactants as model systems to demonstrate that the covalent C−F bonds in RF, which were generally believed to be extremely difficult to reduce, can be unlocked through combined reactant-electrolyte design, with the electrolyte playing a central role in governing activity. The interaction between solvent and fluorinated reactants, such as solvation effects and formation of hydrogen bonds, can alter the electron density distribution along the carbon-fluorine skeleton and weaken fluoride bond strengths as indicated by nuclear magnetic resonance (NMR) spectroscopy and density functional theory (DFT) calculations. As a result, the reduction potential (from galvanostatic measurements for Li cells) can be dramatically increased from < 2.0 V to > 2.9 V vs. Li/Li+ through modulation of the solvent. In addition to activating electrochemically-active pathways, solvent molecules also need to exhibit proper polarities to allow both high miscibility (requiring low polarity), and Li salt solubility (requiring high polarity). Other electrolyte design aspects that can direct the reduction activity of highly fluorinated reactants will also be discussed, including fluoridation of solvent molecules, Li salt dissociation energy, and reactant/salt ratio. These understandings on tuning fluoride bond strength via electrolyte−reactant interactions will open up new design opportunities for fluorinated electrolyte components, either solvents or additives, for Li cells with high cycle stabilities, as well as high-energy Li primary battery with liquid cathodes.

APPLICATION OF THE SCHWENK-PAPA REACTION FOR THE SYNTHESIS OF VICINALLY SUBSTITUTED BICYCLO[2.2.1]HEPTANES

For the first time, the influence of the structure of vicinally substituted bicyclo [2.2.1] heptanes on the yield of hydrogenation products under the Schwenk-Papa reaction conditions was studied. It has been shown that the Schwenk-Papa reaction allows one-step reduction of multiple bonds of the bicyclic fragment, double bonds of side alkyl substituents, as well as nitro- cyano- and oxime groups with their joint presence. At the same time, carboxyl and amide groups are not reduced under these conditions.

Metabolism and Tissue Distribution of Chelerythrine and Effects of Macleaya Cordata Extracts on Liver NAD(P)H Quinone Oxidoreductase

Background: Macleaya cordata (Willd.) (Papaveraceae) is listed as a feed additive in animal production by the European Food Authority.Methods: The metabolites of chelerythrine in rats were measured in vitro and in vivo by rapid and accurate high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS). The structures of CHE metabolites were elucidated by comparing their changes in accurate molecular masses and fragment ions with those of parent ion or metabolite. The metabolic enzymes that were involved in chelerythrine reduction were investigated using an inhibition method. The tissue distribution of chelerythrine and the effects on NQO1 following intragastric administration with M. cordata extracts in rats were examined.Results: A total of twelve metabolites of chelerythrine were characterized by this approach in rat liver S9 and in vivo. The reduction of the iminium bond of chelerythrine and subsequent O-demethylation was the main metabolic pathway of chelerythrine in rat liver S9 while the reduction of the iminium bond of chelerythrine was the main metabolic pathway of chelerythrine in rats in vivo. After the rats were given intragastric administration, the low concentration residues of sanguinarine and chelerythrine in different rat tissues were found at 48 h after the last dose, suggesting that both compounds could be widely distributed in tissues. The results also indicated that XO, NQO1, NQO2, and carbonyl reductase are involved in chelerythrine reduction. Macleaya cordata extracts treated female and male rats, respectively, showed different responses, inhibiting NQO1 activity in males, but inducing NQO1 activity in females. Chelerythrine had a weak impact on NQO1 activity, but sanguinarine inhibited NQO1 activityConclusion: Through studying the effects of cytosolic reductase inhibitors on chelerythrine reduction and the impact of chelerythrine and sanguinarine on the activity of NQO1 in vitro and in vivo, we clarified the potential drug interaction of Macleaya cordata extract in clinical application, so as to provide theoretical guidance for clinically safe medication. In addition, it provided a reference basis for the metabolic mechanism of chelerythrinein rats.

Multiphonon scattering mechanisms to limit thermal conductivity in weberite RE3NbO7: A case study of (La1-xGdx)3NbO7 ceramics

The management of thermal conductivity is of significant scientific interest, particularly for thermal barrier coatings (TBCs). Multifarious strategies have been used to regulate heat transportation, but it is hard to achieve limit thermal conductivity at elevated temperatures. A systematical investigation of weberite (La1-xGdx)3NbO7 was thus performed, and multiphonon scattering mechanisms were introduced to achieve limit thermal conductivity (0.92 W m−1 K−1). Phonon point defect scattering process accounted for thermal conductivity reduction at low temperatures. Additionally, lattice softening strongly contributed to the reduction of high-temperature thermal conductivity, and solid and stiff chemical bonds were beneficial for inhibiting thermal radiative conductivity. A novel strategy was presented to modify thermal transportation property of weberite RE3NbO7 ceramics. Also, the hardness, toughness, and modulus were improved to promote engineering applications of weberite RE3NbO7. This study also illuminates novel paths for thermal management and mechanical properties manipulation of TBCs, thermoelectric materials, and microelectronics.

Using Virtual Screening to Identify Novel Inhibitors for Enoyl‐Acyl Carrier Protein Reductase in Mycobacterium tuberculosis

Mycobacterium tuberculosis causes the highly infectious disease Tuberculosis, an airborne illness primarily affecting the lung which still remains in the top 10 causes of death worldwide, largely due to recent antibiotic resistant tuberculosis strains. InhA, the enoyl-acyl carrier protein reductase, is an advantageous drug target due to its essentiality in M. tuberculosis, as it catalyzes the enoyl-acyl carrier protein double bond reduction. This reaction is an essential precursor to create mycolic acids for cell wall fatty acid biosynthesis. Although there are current antibiotics for this enzyme, many of these once-effective treatments are losing efficacy to the antibiotic-resistant strains, creating a need for novel InhA inhibitors. Using an MtInhA crystallography structure (PDB 4DRE), numerous large libraries of compounds were virtually screened against InhA using the virtual screening program GOLD, Genetic Optimization for Ligand Docking (CCDC). This program uses a genetic algorithm to predict and quantify the binding interactions to estimate the ligand's total binding energy with a relative binding score for each. First, control ligands were docked to validate the GOLD software for compounds known to inhibit MtInhA. After a preliminary screening of tens of thousands of chemical compounds from various libraries was run with a low thoroughness to quickly screen out low-probability hits for MtInhA, the top ten percent of ligands were then screened with higher thoroughness in GOLD, along with additional screening in the programs VINA and ICM. Supplemental filtering using Lipinski's criteria and examination of the best-scoring ligands in the visualization program PyMOL further narrowed down the list. The majority of these top hits were found in the chemical library Novacore, along with a few ligands in the CBZinc library. Novacore's library greatly exceeded the best control ligand scoring 110.93, with scores ranging from 160.09 to 64.4. CBZinc's scores produced a much wider range of scores, from 110.47 to 24.75. These libraries have starkly different binding methods for MtInhA, with Novacore's ligands creating strong binding through a few strong interactions to a small portion of the active site, while CBZinc's ligands create strong binding through numerous interactions which span the entire active site. While the conformations differ greatly, these compounds are noteworthy nonetheless and should be further tested for MtInhA inhibition through wet-lab research.

Role of lysozyme on liquid egg white foaming properties: Interface behavior, physicochemical characteristics and protein structure

Lysozyme separated from egg white has high economic value and plays an important role in biochemistry, medicine and other fields. The role of lysozyme in the foaming properties of egg white was investigated in this study. After lysozyme being removed, the foaming ability (FA) and the foaming stability (FS) of egg white decreased by 45.1% and 35.3%, respectively, while restored again with lysozyme rejoining. In the absence of lysozyme, the particle size decreased and electrostatic repulsion increased, which resulted in a reduction of the protein adsorption on the interface of foam. Meanwhile, FTIR analysis showed the decrease on the protein secondary structure of α-helix and β-sheet. The reduction of hydrogen bonds played an adverse effect on the formation of stable interface. The decreased viscosity indicated the break of ovomucin-lysozyme complex, which was not conducive to the formation of viscoelastic film and leading to a reduction in FS. Furthermore, in the absence of lysozyme, the high surface tension value of the protein was harmful to the adsorption, stretching and rearrangement of protein molecules on the interface. This research provided a new opinion into the effect of lysozyme on the foaming properties of egg white.

Selective C-O Bond Reduction and Borylation of Aryl Ethers Catalyzed by a Rhodium-Aluminum Heterobimetallic Complex.

We report the catalytic reduction of a C-O bond and the borylation by a rhodium complex bearing an X-type PAlP pincer ligand. We have revealed the reaction mechanism based on the characterization of the reaction intermediate and deuterium-labeling experiments. Notably, this novel catalytic system shows steric-hindrance-dependent chemoselectivity that is distinct from conventional Ni-based catalysts and suggests a new strategy for selective C-O bond activation by heterobimetallic catalysis.

High Efficiency RNA Extraction From Sperm Cells Using Guanidinium Thiocyanate Supplemented With Tris(2-Carboxyethyl)Phosphine.

The extraction of high-quality ribonucleic acid (RNA) from tissues and cells is a key step in many biological assays. Guanidinium thiocyanate-phenol-chloroform (AGPC) is a widely used and efficient method to obtain pure RNA from most tissues and cells. However, it is not efficient with some cells like sperm cells because they are resistant to chaotropic lysis solutions containing guanidinium thiocyanate such as Buffer RLT+ and Trizol. Here, we show that disulfide bonds are responsible for the chemical resistance of sperm cells to RNA extraction reagents. We show that while β-mercaptoethanol (βME) can increase sperm lysis in Buffer RLT+, it has no effect in Trizol and leaves sperm cells intact. We measured the reduction of disulfide bonds in 2,2′-dithiodipyridine (DTDP) and observed that βME has a pH-dependent activity in chaotropic solutions, suggesting that pH is a limiting factor. We identified tris(2-carboxyethyl)phosphine (TCEP) as an efficient lysis enhancer of AGPC solutions that can retain reducing activity even at acidic pH. Trizol supplemented with TCEP allows the complete and rapid lysis of sperm cells, increasing RNA yield by 100-fold and resulting in RNA with optimal quality for reverse transcription and polymerase chain reaction. Our findings highlight the importance of efficient cell lysis and extraction of various macromolecules for bulk and single-cell assays, and can be applied to other lysis-resistant cells and vesicles, thereby optimizing the amount of required starting material and animals.

Reduction-Responsive Anticancer Nanodrug Using a Full Poly(ethylene glycol) Carrier.

Poly(ethylene glycol) (PEG) is applied extensively in biomedical fields because of its nontoxic, nonimmunogenic, and protein resistance properties. However, the strong hydrophilicity of PEG prevents it from self-assembling into an amphiphilic micelle in water, making it a challenge to fabricate a full-PEG carrier to deliver hydrophobic anticancer drugs. Herein, a paclitaxel (PTX)-loaded nanodrug was readily prepared through self-assembly of PTX and an amphiphilic PEG derivative, which was synthesized via melt polycondensation of two PEG diols (i.e., PEG200 and PEG10k) and mercaptosuccinic acid. The full PEG component endows the nanocarrier with good biocompatibility. Furthermore, because of the core cross-linked structure via the oxidation of mercapto groups, the nanodrug can be selectively disassociated under an intratumor reductive microenvironment through the reduction of disulfide bonds to release the loaded PTX and kill the cancer cells while maintaining high stability under the extratumor physiological condition. Additionally, it was confirmed that the nanodrug not only prolongs the biocirculation time of PTX but also possesses excellent in vivo antitumor efficacy while avoiding side effects of free PTX, for example, liver damage, which is promising for delivering clinical hydrophobic drugs to treat a variety of malignant tumors.

Disulfide bond based cascade reduction-responsive Pt(IV) nanoassemblies for improved anti-tumor efficiency and biosafety

The platinum-based drugs prevail in the therapy of malignant tumors treatment. However, their clinical outcomes have been heavily restricted by severe systemic toxicities. To ensure biosafety and efficiency, herein, we constructed a disulfide bond inserted Pt(IV) self-assembled nanoplatform that is selectively activated by rich glutathione (GSH) in tumor site. Disulfide bond was introduced into the conjugates of oxaliplatin (IV) and oleic acid (OA) which conferred cascade reduction-responsiveness to nanoassemblies. Disulfide bond cleavage and reduction of Pt(IV) center occur sequentially as a cascade process. In comparison to oxaliplatin solution, Pt(IV) nanoparticles (NPs) achieved prolonged blood circulation and higher maximum tolerated doses. Furthermore, Oxa(IV)-SS-OA prodrug NPs exhibited potent anti-tumor efficiency against 4T1 cells and low toxicities in other normal tissues, which offers a promising nano-platform for potential clinical application.

A unique leucine-valine adhesive motif supports structure and function of protein disulfide isomerase P5 via dimerization

P5, also known as PDIA6, is a PDI family member involved in the ER quality control. Here, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. Unlike conventional leucine zipper motifs with leucine residues every two helical turns on ∼30-residue parallel α helices, this adhesive motif includes periodic repeats of leucine/valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel α helices. The P5 dimerization interface is further stabilized by several reciprocal salt bridges and C-capping interactions between protomers. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as aberrant proteins that induce the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1α via intermolecular disulfide bond reduction and its Ca2+-dependent regulation of chaperone function invitro. Thus, the leucine-valine adhesive motif supports structure and function of P5.