Delocalization Engineering of Heme-Mimetic Artificial Enzymes for Augmented Reactive Oxygen Catalysis.

Developing artificial enzymes based on organic molecules or polymers for reactive oxygen species (ROS)-related catalysis has broad applicability. Herein, inspired by porphyrin-based heme mimics, we report the synthesis of polyphthalocyanine-based conjugated polymers (Fe-PPc-AE) as a new porphyrin-evolving structure to serve as efficient and versatile artificial enzymes for augmented reactive oxygen catalysis. Owing to the structural advantages, such as enhanced π-conjugation networks and π-electron delocalization, promoted electron transfer, and unique Fe-N coordination centers, Fe-PPc-AE showed more efficient ROS-production activity in terms of Vmax and turnover numbers as compared with porphyrin-based conjugated polymers (Fe-PPor-AE), which also surpassed reported state-of-the-art artificial enzymes in their activity. More interestingly, by changing the reaction medium and substrates, Fe-PPc-AE also revealed significantly improved activity and environmental adaptivity in many other ROS-related biocatalytic processes, validating the potential of Fe-PPc-AE to replace conventional (poly)porphyrin-based heme mimics for ROS-related catalysis, biosensors, or biotherapeutics. It is suggested that this study will offer essential guidance for designing artificial enzymes based on organic molecules or polymers.

Metal-oxo Cluster Mediated Atomic Rh with High Accessibility for Efficient Hydrogen Evolution.

Achieving single-atom catalysts (SACs) with high metal content and outstanding performance as well as robust stability is critically needed for clean and sustainable energy. However, most of the synthesized SACs are undesired on the loading content of the metal due to the anchored metals and the supports as well as the synthesizing methods. Herein, a Rh-SAC with high accessibility by loading it on the metal nodes of metal-porphyrin-based PCN MOFs (PCN-224) as supporting material is reported. Significantly, the PCN-Rh15.9 /KB catalyst with a high Rh content of 15.9 wt% exhibits excellent hydrogen evolution activity with a low overpotential of 25 mV at a current density of 10 mA cm-2 and a mass activity of 7.7 A mg-1 Rh at overpotential of 150 mV, which is much better than that of the commercial Rh/C. Various characterizations reveal the Rh species is stabilized by the metal nodes bearing -O/OHx in MOFs, which is of importance for the high loading amount and the good activity. This work establishes an efficient approach to synthesize high content SACs on the nodes of MOFs for wide catalyst design.

Semiconducting Titanate Supported Ruthenium Clusterzymes for Ultrasound-Amplified Biocatalytic Tumor Nanotherapies.

The external-stimulation-induced reactive-oxygen-species (ROS) generation has attracted increasing attention in therapeutics for malignant tumors. However, engineering a nanoplatform that integrates with efficient biocatalytic ROS generation, ultrasound-amplified ROS production, and simultaneous relief of tumor hypoxia is still a great challenge. Here, we create new semiconducting titanate-supported Ru clusterzymes (RuNC/BTO) for ultrasound-amplified biocatalytic tumor nanotherapies. The morphology and chemical/electronic structure analysis prove that the biocatalyst consists of Ru nanoclusters that are tightly stabilized by Ru-O coordination on BaTiO3 . The peroxidase (POD)- and halogenperoxidase-like biocatalysis reveals that the RuNC/BTO can produce abundant •O2 - radicals. Notably, the RuNC/BTO exhibits the highest turnover number (63.29 × 10-3 s-1 ) among the state-of-the-art POD-mimics. Moreover, the catalase-like activity of the RuNC/BTO facilitates the decomposition of H2 O2 to produce O2 for relieving the hypoxia of the tumor and amplifying the ROS level via ultrasound irradiation. Finally, the systematic cellular and animal experiments have validated that the multi-modal strategy presents superior tumor cell-killing effects and suppression abilities. We believe that this work will offer an effective clusterzyme that can adapt to the tumor microenvironment-specific catalytic therapy and also provide a new pathway for engineering high-performance ROS production materials across broad therapeutics and biomedical fields.

Ultralow Ru Single Atoms Confined in Cerium Oxide Nanoglues for Highly-Sensitive and Robust H2 O2 -Related Biocatalytic Diagnosis.

Exploring highly efficient, portable, and robust biocatalysts is a great challenge in colorimetric biosensors. To overcome the challenging states in creating single-atom biocatalysts, such as insufficient activity and stability, here, this work has engineered a unique CeO2 support as nanoglue to tightly anchor the Ru single-atom sites (CeO2 -Ru) with strong electronic coupling for achieving highly sensitive and robust H2 O2 -related biocatalytic diagnosis. The morphology and chemical/electronic structure analysis demonstrates that the Ru atoms are well-dispersed on CeO2 surface to form high-density active sites. Benefiting from the unique structure, the prepared CeO2 -Ru exhibits outstanding peroxidase (POD) like catalytic activity and selectivity to H2 O2 . Steady-state kinetic study results show that the CeO2 -Ru presents the highest Vmax and turnover number than the state-of-the-art POD-like biocatalysts. Consequently, the CeO2 -Ru discloses a high efficiency, good selectivity, and robust stability in the colorimetric detection of L-cysteine, glucose, and uric acid. Notably, the limit of detection (LOD) can reach 0.176 × 10-3 m for the L-cysteine, 0.095 × 10-3 m for the glucose, and 0.088 × 10-3 m for the uric acid via cascade reaction. This work suggests that the proposed unique CeO2 nanoglue will offer a new path to create single-atom noble metal biocatalysts and take a step closer to future biotherapeutic and biocatalytic applications.

Modulating Electronic Environment of Ru Nanoclusters via Local Charge Transfer for Accelerating Alkaline Water Electrolysis.

Compared to platinum catalysts, ruthenium (Ru) is disclosed as a promising alternative for alkaline water electrolysis due to its similar hydrogen adsorption energy and relatively lower water dissociation barrier. However, in the challenging alkaline media, the dissatisfied Volmer step during water dissociation of Ru metal prohibits its practical applications. Here, a new pathway to modulate the electronic environment of Ru catalysts via a local charge transfer strategy for tuning the water dissociation kinetics and accelerating the alkaline water electrolysis is proposed. The obtained catalysts are engineered by assembling and subsequently pyrolyzing the layer-stacked and 2D porphyrin-based Ru-N coordination polymers on nanocarbon supports. Benefiting from the well-defined Ru nanocluster-Nx -coordination bonds (Runc -Nx ), unique electronic environments, and local charge transfer properties, the catalysts exhibit the exceptional activity of 17 mV overpotential at 10 mA cm-2 and robust stability in water, which is more efficient than state-of-the-art Ru catalysts. The theoretical calculation suggests that the Runc -Nx sites enhance the nucleophilic attack of water and weaken the HOH bond. This study manifests that tailoring the bond environments of Ru clusters can significantly modulate their intrinsic catalytic activities and stabilities, which may open new avenues for developing high-active and durable catalysts for water electrolysis.

Electronic Structure-Dependent Water-Dissociation Pathways of Ruthenium-Based Catalysts in Alkaline H2 -Evolution.

Ruthenium (Ru)-based catalysts have displayed compelling hydrogen evolution activities, which hold the promising potential to substitute platinum in alkaline H2 -evolution. In the challenging alkaline electrolytes, the water-dissociation process involves multistep reactions, while the profound origin and intrinsic factors of diverse Ru species on water-dissociation pathways and reaction principles remain ambiguous. Here the fundamental origin of water-dissociation pathways of Ru-based catalysts in alkaline media to be from their unique electronic structures in complex coordination environments are disclosed. These theoretical results validate that the modulated electronic structures with delocalization-localization coexistence at their boundaries between the Ru nanocluster and single-atom site have a profound influence on water-dissociation pathways, which push H2 O* migration and binding orientation during the splitting process, thus enhancing the dissociation kinetics. By creating Ru catalysts with well-defined nanocluster, single-atom site, and also complex site, the electrocatalytic data shows that both the nanocluster and single-atom play essential roles in water-dissociation, while the complex site possesses synergistically enhanced roles in alkaline electrolytes. This study discloses a new electronic structure-dependent water-dissociation pathway and reaction principle in Ru-based catalysts, thus offering new inspiration to design efficient and durable catalysts for the practical production of H2 in alkaline electrolytes.

Manganese-Based Antioxidase-Inspired Biocatalysts with Axial Mn-N5 Sites and 2D d-π-Conjugated Networks for Rescuing Stem Cell Fate.

Constructing highly effective biocatalysts with controllable coordination geometry for eliminating reactive oxygen species (ROS) to address the current bottlenecks in stem-cell-based therapeutics remains challenging. Herein, inspired by the coordination structure of manganese-based antioxidase, we report a manganese-coordinated polyphthalocyanine-based biocatalyst (Mn-PcBC) with axial Mn-N5 sites and 2D d-π-conjugated networks that serves as an artificial antioxidase to rescue stem cell fate. Owing to the unique chemical and electronic structures, Mn-PcBC displays efficient, multifaceted, and robust ROS-scavenging activities, including elimination of H2 O2 and O2 ⋅- . Consequently, Mn-PcBC efficiently rescues the bioactivity and functionality of stem cells in high-ROS-level microenvironments by protecting the transcription of osteogenesis-related genes. This study offers essential insight into the crucial functions of axially coordinated Mn-N5 sites in ROS scavenging and suggests new strategies to create efficient artificial antioxidases for stem-cell therapies.

π-Conjugated Copper Phthalocyanine Nanoparticles as Highly Sensitive Sensor for Colorimetric Detection of Biomarkers.

Though numerous nanomaterials with enzyme-like activities have been utilized as probes and sensors for detecting biological molecules, it is still challenging to construct highly sensitive detectors for biomarkers using polymeric materials. Benefiting from the π-d delocalization effect of electrons, excellent metal-chelating property, high electron transferability, and good chemical stability of π-conjugated phthalocyanine, the design of the copper phthalocyanine-based conjugated polymer nanoparticles (Cu-PcCP NPs) as a colorimetric sensor for a variety of biomarkers is reported. The Cu-PcCP NPs are synthesized through a simple microwave-assisted polymerization, and their chemical structures are thoroughly characterized. The colorimetric results of Cu-PcCP NPs demonstrate excellent peroxidase-like detecting activity and also great substrate selectivity than most of the reported Cu-based nanomaterials. The Cu-PcCP NPs can achieve a detection limit of 4.88 µM for the H2 O2 , 4.27 µM for the L-cysteine, and 21.10 µM for the glucose via a cascade catalytic system, which shows comparable detecting sensitivity as that of many earlier reported enzyme-like nanomaterials. Moreover, Cu-PcCP NPs present remarkable resistance to harsh conditions, including high temperature, low pH, and excessive salts. These highly specific π-conjugated copper-phthalocyanine nanoparticles not only overcome the current limitation of polymeric material-based sensors but also provide a new direction for designing next-generation enzyme-like nanomaterial-based colorimetric biosensors.

[A photothermal/chemotherapy injectable paclitaxel gel with irradiation stability].

The aim of this study is to construct an injectable gel with stable phototherapy and chemotherapy. Res-PTX@IR780 gel with phototherapy and chemotherapy property was prepared by introduction of photosensitizer IR780 and antioxidant resveratrol (Res) into the polyethylene glycol (PEG) solution of paclitaxel (PTX). The results showed that PTX, PTX@IR780 and Res-PTX@IR780 could form gels and the gels were injectable. ATR-FTIR results indicated not only components of the gels but also the formation of hydrogen bonding during the gelation. The results of UV showed instability of IR780 solution and stability improvement of Res-IR780 solution under infrared radiation (IR) irradiation. Photothermal tests showed that Res-PTX@IR780 displayed better photothermal conversion and photothermal stability under multiple irradiations than PTX@IR780. The results of in vivo exploration in mice showed that the skin site injected with Res-PTX@IR780 gel heated up from 35 ℃ to 64 ℃, and the temperature difference was up to 30 ℃. Res-PTX@IR780 gel is very promising as a combination agent of photothermal therapy and chemotherapy for the in situ treatment of tumors due to good photothermal conversion and photothermal stability under multiple irradiations.

Exogenous Vitamin C-Triggered Surface Charge Conversion of pH/Reduction-Responsive Micelles for the Enhanced Tumor-Specific Activity of Loaded Doxorubicin.

The effective accumulation at tumor sites and endocytosis by tumor cells for anticancer agents in carriers are essential in successful cancer therapy, and both of the processes are affected by the surface charge of drug carriers. In this study, vitamin C (VC) was employed as an "exogenous switch" to trigger the surface charge conversion of DOX-loaded micelles to obtain a better antitumor effect. T micelles formed by poly(ε-caprolactone)-b-poly(N,N-diethylaminoethyl methacrylate)-ss-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PCL-PDEA-ss-PMPC) turned their ζ potentials from +1 mV to +18 mV under treatment of 20 mM VC, while the ζ potentials of control R micelles formed by PCL-ss-P(DEA-r-MPC) almost remained unchanged under the same condition. DOX-loaded T@DOX and R@DOX had high DLCs of 12% and 13.8%, respectively, and both showed an accelerated drug release in a reductive environment (10 mM GSH or 20 mM VC) at pH 5.0. Notably, due to the surface charge conversion and fast drug release triggered by VC, T@DOX/VC (T@DOX was pretreated by VC) showed an enhanced cytotoxicity and cellular uptake superior to T@DOX, R@DOX, and R@DOX/VC. T@DOX/VC also displayed the in vivo antitumor effect well, which was comparable to DOX·HCl but with less toxic side effects than DOX·HCl. In summary, VC as an exogenous trigger can induce a better antitumor effect of drug-loaded micelles with a suitable polymer structure by charge conversion, and T@DOX/VC has shown to be as a promising approach to achieve potent treatment of tumors.

Metal-Free Oxidative Esterification of Ketones and Potassium Xanthates: Selective Synthesis of α-Ketoesters and Esters.

A novel and efficient oxidative esterification for the selective synthesis of α-ketoesters and esters has been developed under metal-free conditions. In the protocol, various α-ketoesters and esters are available in high yields from commercially available ketones and potassium xanthates. Mechanistic studies have proven that potassium xanthate not only promotes oxidative esterification but also provides an alkoxy moiety for the reaction, which involves the cleavage and reconstruction of C-O bonds.

Interleukin-33 Promotes Th2/Th17 Response in Eosinophilic and Non-Eosinophilic Nasal Polyps.

BACKGROUND: Interleukin-33 (IL-33) is reported to be involved in Th2-skewed eosinophilic inflammation. A recent study also found that IL-33 exerted opposite effects on Th17 response in different diseases. However, the role of IL-33 in chronic rhinosinusitis with nasal polyps (NPs) was not explored. OBJECTIVES: The purpose of this study was to investigate the expression and function of IL-33 in chronic rhinosinusitis with NPs. MATERIALS AND METHODS: NP tissues from 60 NP patients and normal tissues of the inferior turbinate from 20 controls were sampled in operation. Immunochemistry was performed to identify eosinophilic or non-eosinophilic NPs. The expressions of IL-33 and Th1/2/17 cytokines were compared between different subtypes of NPs. The effect of IL-33 on Th response was detected in dispersed nasal polyp cells (DNPCs), and the signaling pathways involved in the process were detected using Western blot. RESULTS: The concentration of IL-33 was significantly elevated in both eosinophilic and non-eosinophilic NPs compared with controls. By in vitro study, we found that IL-33 can induce IL-4 and IL-5 production from eosinophilic DNPCs through the PI3K/AKT pathway, whereas IL-33 can induce IL-17 production from non-eosinophilic DNPCs through the ERK1/2 pathway. CONCLUSION: IL-33 is involved in Th2/Th17 response in NPs. Our study suggests that different types of NPs need a different treatment target.

(Z)-Tetrahydrothiophene and (Z)-tetrahydrothiopyran synthesis through nucleophilic substitution and intramolecular cycloaddition of alkynyl halides and EtOCS2K.

This protocol provides a novel, environmentally friendly and simple method for the synthesis of (Z)-tetrahydrothiophene derivatives using the nucleophilic thiyl radical intramolecular cycloaddition cascade process to construct C-S bonds under transition-metal-free conditions. This transformation process offers a broad substrate scope, good functional group tolerance, and excellent stereoselectivity (Z/E ratios up to 99/1). Moreover, the process uses odourless, stable and cheap EtOCS2K as the sulfur source.

2-Acetylthienopyridine Synthesis via Thiolation and Copper-Catalyzed Cyclization of o-Propynol Fluoropyridine Using Xanthate as a Thiol Surrogate.

2-Acylthienopyridines and related heterocycles are readily prepared in moderate to good yields under mild conditions by a nucleophilic thiolation, copper-catalyzed cyclization, and an oxidation cascade process using potassium xanthate as the thiol source. Moreover, excellent chemoselectivity, broad substrate scope, and good functional group tolerance are prominent features of this transformation.

Annexin V-Conjugated Mixed Micelles as a Potential Drug Delivery System for Targeted Thrombolysis.

To alleviate the hemorrhagic side effect of thrombolysis therapy, a thrombus targeted drug delivery system based on the specific affinity of Annexin V to phosphatidylserine exposed on the membrane surface of activated platelet was developed. The amphiphilic and biodegradable biomaterial, polycaprolactone-block-poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-hydroxyethyl methacrylate) (PCL-b-PDMAEMA-b-PHEMA (PCDH)) triblock polymer, was synthesized via ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) to use as the nanocarriers of thrombolytic drug. In order to conjugate Annexin V to the polymer, PCDH was modified by succinic anhydride via ring-opening reaction to introduce the carboxyl group (PCDH-COOH). After preparation of PCDH/PCDH-COOH (9/1, m/m) mixed micelles, Annexin V was coupled with the micelles using carbodiimide chemistry. The blood clot lysis assay in vitro confirmed that lumbrokinase-loaded targeted micelles (LKTM) had stronger thrombolysis potency than free lumbrokinase (LK) and LK-loaded nontargeted micelles (LKM, P < 0.05). In vivo thrombolytic assay, multispectral, optoacoustic tomography (MSOT) was used to assess the target ability of LKTM. The results of MSOT images indicated the fluorescence intensity of the LKTM group located in the blood clot position were significantly stronger than the LKM group. A 5 mm of carotid artery containing blood clot was cut out 24 h later after administration to assess the degree of thrombolysis. The results of thrombolytic assay in vivo were consistent with the assay in vitro, which the differences between LK, LKM, and LKTM groups were both statistically significant. All the results of thrombolysis assays above proved that the capacity of thrombolysis in the LKTM group was optimal. It suggested that Annexin V-conjugated micelles will be a potential drug delivery system for targeted thrombolysis.

The anti-bacterial poly(caprolactone)-poly(quaternary ammonium salt) as drug delivery carriers.

Anti-bacterial materials play significant role in biomedical field. Researches and applications of new anti-bacterial materials are necessary. Novel linear and star-shaped copolymers of poly(caprolactone)-poly(quaternary ammonium salt) (PCL-PJDMA) were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structures of the copolymers were confirmed by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. The copolymers self-assembled into ball-shaped micelles with low critical micelle concentration (10(-4) ∼ 10(-3) mg/ml). An anti-bacterial drug, triclosan, was chosen as a model drug to investigate the potential application of the copolymers in drug-controlled release. The anti-bacterial experiments against Escherichia coli indicated that all the copolymer micelles had anti-bacterial ability and drug-loaded star-shaped PCL-PJDMA micelles were the best. The slow release of the drug from the drug-loaded micelles prolonged anti-bacterial effect. Therefore, PCL-PJDMA themselves have not only anti-bacterial ability but also the copolymer micelles can be used as carriers for anti-bacterial drugs.

Ruthenium-Catalyzed C-H Arylation of Aromatic Acids with ortho-Haloaniline To Access Phenanthridinones.

Phenanthridinone is a significant moiety in pharmaceutical and material science; thus, it is highly desirable to develop an efficient and robust method to construct phenanthridinone from readily available starting materials. Herein, we report a Ru-catalyzed C-H arylation of aromatic carboxylic acids with ortho-haloanilines, followed by intramolecular dehydration to afford phenanthridinones in high yields.

Multifunctional Therapeutic Nanodiamond Hydrogels for Infected-Wound Healing and Cancer Therapy.

Wound infection and tumor recurrence are the two main threats to cancer patients after surgery. Although researchers have developed new treatment systems to address the two significant challenges simultaneously, the potential side effects of the heavy-metal-ion-based treatment systems still severely limit their widespread application in therapy. In addition, the wounds from tumor removal compared with general operative wounds are more complex. The tumor wounds mainly exhibit more hemorrhage, larger trauma area, greater vulnerability to bacterial infection, and residual tumor cells. Therefore, a multifunctional treatment platform is urgently needed to integrate rapid hemostasis, sterilization, wound healing promotion, and antitumor functions. In this work, nanodiamonds (NDs), a material that has been well proven to have excellent biocompatibility, are added into a solution of acrylic-grafted chitosan (CEC) and oxidized hyaluronic acid (OHA) to construct a multifunctional treatment platform (CEC-OHA-NDs). The hydrogels exhibit rapid hemostasis, a wound-healing-promoting effect, excellent self-healing, and injectable abilities. Moreover, CEC-OHA-NDs can effectively eliminate bacteria and inhibit tumor proliferation by the warm photothermal effect of NDs under tissue-penetrable near-infrared laser irradiation (NIR) without cytotoxicity. Consequently, we adopt a simple and convenient strategy to construct a multifunctional treatment platform using carbon-based nanomaterials with excellent biocompatibility to promote the healing of infected wounds and to inhibit tumor cell proliferation simultaneously.

Effect of serum inflammatory factors in predicting co-infection with influenza viruses and Omicron.

OBJECTIVES: To identify the key differences in laboratory indicators between mono-infection and co-infection by influenza viruses and Omicron to facilitate timely adjustments in patient treatment strategies. METHODS: Prealbumin and C-reactive protein (CRP) levels were analyzed in 161 COVID-19 cases infected by SARS-CoV-2 (wild type), 299 cases infected by Omicron, 95 cases infected by influenza virus A/B (Flu A/B) and 133 co-infection cases infected with Flu A/B and Omicron. The receiver operating characteristic (ROC) curve and logistic regression equation were used to analyze the clinical predictive capacity of prealbumin and CRP in coinfected patients. RESULTS: The co-infected and wild-type infected patients had significantly different CRP and prealbumin levels compared to mono-infected patients with Omicron or Flu A/B (p < .001). The ROC curve results indicated that prealbumin was more efficient than CRP in identifying co-infection from Omicron (AUC: 0.867 vs. 0.724) or Flu A/B (AUC: 0.797 vs. 0.730), and joint prediction significantly improved the diagnostic ability to discriminate co-infection from mono-infection (AUC: 0.934 and 0.887). CONCLUSION: The findings suggest that prealbumin is a valuable indicator that can warn of co-infection and guide timely treatment decisions. Joint prediction may offer an even more effective diagnostic tool for discriminating co-infection from mono-infection.

Ligand-enabled ruthenium-catalyzed meta-C-H alkylation of (hetero)aromatic carboxylic acids.

Carboxylates are ideal directing groups because they are widely available, readily cleavable and excellent linchpins for diverse follow-up reactions. However, their use in meta-selective C-H functionalizations remains a substantial unmet catalytic challenge. Herein, we report the ruthenium-catalyzed meta-C-H alkylation of aromatic carboxylic acids with various functionalized alkyl halides. A bidentate N-ligand increases the electron density at the metal center of ortho-benzoate ruthenacycles to the extent that single-electron reductions of alkyl halides can take place. The subsequent addition of alkyl radicals is exclusively directed to the position para to the CAr-Ru bond, i.e., meta to the carboxylate group. The resulting catalytic meta-C-H alkylation extends to a wide range of (hetero)aromatic carboxylic acids including benzofused five-membered ring heteroarenes but no pyridine derivatives in combination with secondary/tertiary alkyl halides, including fluorinated derivatives. It also allows site-selective C5-H alkylation of 1-naphthoic acids. The products are shown to be synthetic hubs en route to meta-alkylated aryl ketones, nitriles, amides, esters and other functionalized products.