Axial O Atom-Modulated Fe(III)-N4 Sites for Enhanced Cascade Catalytic 1O2-Induced Tumor Therapy.

The rational construction of efficient hypoxia-tolerant nanocatalysts capable of generating singlet oxygen (1O2) without external stimuli is of great importance for tumor therapy. Herein, uniformly dispersed and favorable biosafety profile graphitic carbon nitride quantum dots immobilized with Fe-N4 moieties modulated by axial O atom (denoted as O-Fe-N4) are developed for converting H2O2 into 1O2 via Russell reaction, without introducing external energy. Notably, O-Fe-N4 performs two interconnected catalytic properties: glutathione oxidase-mimic activity to provide substrate for subsequent 1O2 generation, avoiding the blunting anticancer efficacy by glutathione. The O-Fe-N4 catalyst demonstrates a specific activity of 79.58 U mg-1 at pH 6.2, outperforming the most reported Fe-N4 catalysts. Density functional theory calculations demonstrate that the axial O atom can effectively modulate the relative position and electron affinity between Fe and N, lowering the activation energy, strengthening the selectivity, and thus facilitating the Russell-type reaction. The gratifying enzymatic activity stemming from the well-defined Fe-N/O structure can inhibit tumor proliferation by efficiently downregulating glutathione peroxidase 4 activity and inducing lipid peroxidation. Altogether, the O-Fe-N4 catalyst not only represents an efficient platform for self-cascaded catalysis to address the limitations of 1O2-involved cancer treatment but also provides a paradigm to enhance the performance of the Fe-N4 catalyst.

Isolation and characterization of a hepatoprotective polysaccharide from Lonicera caerulea L. var. edulis Turcz. ex Herd. fruit against APAP-induced acute liver injury mice.

The structure and bioactivities of a novel polysaccharide from Lonicera caerulea L. var. edulis Turcz. ex Herd. fruit (THP-3) were investigated. The crude polysaccharides of Turcz. ex Herd. (THP) were extracted by hot water extraction. After purification, the chemical structure of polysaccharides was identified. Then, a mouse model of acute drug-induced liver injury was constructed using 4-acetamidophenol (APAP) and pretreated with THP. The number-average molecular weight of THP-3 was 48.89 kDa and the mass average molar mass was 97.87 kDa. THP-3 was mainly composed of arabinose (42.54 %), glucose (27.62 %), galacturonic acid and galactose (29.84 %). The main linkage types of THP-3 were 1-linked Araf, 1,4-linked Glcp, and 1,3,6-linked Galp. In addition, after THP treatment, serum Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGT) in AILI mice were successfully down-regulated. The results showed that THP could prevent the characteristic morphological changes of hepatic lobular injury and lipid depletion caused by APAP, reduced the level of oxidative damage in mice, increased the expression of APAP-induced hypolipidemia and related inflammatory indicators, and improved the detoxification function of liver. In general, the newly extracted THP polysaccharide has a good liver protection effect and is an ideal natural medicine for the treatment of liver diseases.

Multifunctional fluorescence/photoacoustic bimodal imaging of γ-glutamyltranspeptidase in liver disorders under different triggering conditions.

Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.

Near-infrared imaging of hepatocellular carcinoma and its medicinal treatment with a γ-glutamyl transpeptidase-monitoring fluorescence probe.

Herein, the Near-infrared imaging of hepatocellular carcinoma (HCC) and its medicinal treatment was achieved with a γ-glutamyl transpeptidase (GGT)-monitoring fluorescence probe KYZ-GGT which consisted of the typical recognition group γ-glutamyl and the structurally modified signal reporting group hemicyanine-thioxanthene. Compared with the recently reported probes, KYZ-GGT suggested practical and steady capability for monitoring the GGT level in the cellular, xenograft, induced as well as medicinal treatment HCC models. It realized the mitochondrial targeting intracellular imaging to reflect the GGT dynamics in the induction or medicinal treatment of HCC. In the xenograft and induced model mice with multiple factors, KYZ-GGT showed stable performance for visualizing the HCC status. In the medicinal treatment of the long-period-induced HCC model mice verified by the serum indexes and histopathological analysis, KYZ-GGT successfully imaged the medicinal treatment process of HCC with two marketed drugs (Sorafenib and Lenvatinib) respectively, with an applicative penetration depth. The information here was meaningful for investigating effective medicinal strategies for overcoming HCC.

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation.

CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through π-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines.

Hydrophobic Carbon Dots Derived from Organic Pollutants and Applications in NIR Anticounterfeiting and Bioimaging.

In an effort to fulfill the strategy of sustainable development, Rhodamine B, a common and toxic organic pollutant in the textile industry, was reported for the first time as a single precursor to develop a kind of novel hydrophobic nitrogen-doped carbon dot (HNCD) through a green and facile one-pot solvothermal method. The HNCDs with an average size of 3.6 nm possess left and right water contact angles of 109.56° and 110.34°, respectively. The HNCDs manifest excitation wavelength-tunable and upconverted fluorescence from the ultraviolet (UV) to the near-infrared (NIR) range. Furthermore, the PEGylation of HNCDs enables them to be used as an optical marker for cell and in vivo imaging. Notably, the HNCDs with solvent-dependent fluorescence can be used for invisible inks with a wide range of light responses from UV-vis-NIR spectra. This work not only provides an innovative way to recycle chemical waste but also expands the potential application of HNCDs in NIR security printing and bioimaging.

Process Optimization of Dual-Liquid Casting and Interfacial Strength-Toughness of the Produced LAS/HCCI Bimetal.

The pouring time interval is the decisive factor of dual-liquid casting for bimetallic productions. Traditionally, the pouring time interval is fully determined by the operator's experience and on-site observation. Thus, the quality of bimetallic castings is unstable. In this work, the pouring time interval of dual-liquid casting for producing low alloy steel/high chromium cast iron (LAS/HCCI) bimetallic hammerheads is optimized via theoretical simulation and experimental verification. The relevancies of interfacial width and bonding strength to pouring time interval are, respectively, established. The results of bonding stress and interfacial microstructure indicate that 40 s is the optimum pouring time interval. The effects of interfacial protective agent on interfacial strength-toughness are also investigated. The addition of the interfacial protective agent yields an increase of 41.5% in interfacial bonding strength and 15.6% in toughness. The optimum dual-liquid casting process is used to produce LAS/HCCI bimetallic hammerheads. Samples cut from these hammerheads show excellent strength-toughness (1188 Mpa for bonding strength and 17 J/cm2 for toughness). The findings could be a reference for dual-liquid casting technology. They are also helpful for understanding the formation theory of the bimetal interface.

Detection of type III effector-induced transcription factors that regulate phytohormone content during symbiosis establishment in soybean.

Soybean is a pivotal protein and oil crop that utilizes atmospheric nitrogen via symbiosis with rhizobium soil bacteria. Rhizobial type III effectors (T3Es) are essential regulators during symbiosis establishment. However, how the transcription factors involved in the interaction between phytohormone synthesis and type III effectors are connected is unclear. To detect the responses of phytohormone and transcription factor genes to rhizobial type III effector NopAA and type III secretion system, the candidate genes underlying soybean symbiosis were identified using RNA sequencing (RNA-seq) and phytohormone content analysis of soybean roots infected with wild-type Rhizobium and its derived T3E mutant. Via RNA-seq analysis the WRKY and ERF transcription factor families were identified as the most differentially expressed factors in the T3E mutant compared with the wild-type. Next, qRT-PCR was used to confirm the candidate genes Glyma.09g282900, Glyma.08g018300, Glyma.18g238200, Glyma.03g116300, Glyma.07g246600, Glyma.16g172400 induced by S. fredii HH103, S. fredii HH103ΩNopAA, and S. fredii HH103ΩRhcN. Since the WRKY and ERF families may regulate abscisic acid (ABA) content and underlying nodule formation, we performed phytohormone content analysis at 0.5 and 24 h post-inoculation (hpi). A significant change in ABA content was found between wild Rhizobium and type III effector mutant. Our results support that NopAA can promote the establishment of symbiosis by affecting the ABA signaling pathways by regulating WRKY and ERF which regulate the phytohormone signaling pathway. Specifically, our work provides insights into a signaling interaction of prokaryotic effector-induced phytohormone response involved in host signaling that regulates the establishment of symbiosis and increases nitrogen utilization efficiency in soybean plants.

Discovered two polymorphs and two solvates of lamotrigine-tolfenamic acid salt: Thermal behavior and crystal morphological differences.

Multi-component pharmaceutical systems such as cocrystal and salt have gained popularity in academia and industry due to their ability to regulate the poor physicochemical properties of active pharmaceutical ingredients (APIs). However, different crystal states, namely polymorphs are becoming a key factor influencing future clinical drug safety. It remains an under explored field, particularly how to hit the polymorphs of multi-components system quickly and effectively. For the first time, a novel drug-drug salt of lamotrigine (LAM)-tolfenamic acid (TOL) with two polymorphs and two solvates were discovered in this study. Forms I and II exist in rhombohedral and block crystal morphologies, whereas methanol and ethanol solvates are crystallized as rods and flakes, respectively. Further physicochemical properties were characterized and compared between parent compounds and the four crystal forms. The apparent solubilities of the new four crystal forms were higher than TOL but lower than LAM. The intrinsic dissolution rates of all crystal forms at 37.0 °C followed a similar trend, and all crystal forms were non-hygroscopic (<1.0%). Two stable polymorphs provide a new choice for the further formulation development.

NIR-II responsive PEGylated nickel nanoclusters for photothermal enhanced chemodynamic synergistic oncotherapy.

Rationale: All kinds of non-metal and metal-based nanozymes have been extensively explored as Fenton agents for Chemodynamic therapy (CDT). However, the low catalytic efficiency of non-metallic nanozymes and the susceptibility to oxidation and long-term toxicity of metallo-nanozymes limit their potential in CDT. Methods: In this study, we report a magneto-solvothermal method to tune the crystallinity and shape of polyethylene glycol (PEG)-ylated urchin-like nickel nanoclusters (named as 9T-PUNNC) at a high magnetic field with an intensity of 9 T for enhanced combined photothermal-chemodynamic therapy. Results: The needle-like protrusions on the surface of 9T-PUNNC can effectively increase the reception of NIR light in second NIR window (NIR-II) and transform it into local hyperthermia, achieving effective photothermal treatment. The light and heat generated by NIR-II further promotes the release of Ni2+ and improves the ability of Ni2+-mediated chemodynamic therapy (CDT). In addition, the surface coating of PEG on the surface of 9T-PUNNC improves its stability and biocompatibility of nanocrystals. In vitro and in vivo results indicate that the 9T-PUNNC could efficiently kill tumor cells (nearly 12 times more than control group) and inhibit tumor growth (nearly 9 times smaller than control group) under NIR-II irradiation through the synergistic effect of combined treatments. Conclusions: we developed a novel synthetic strategy to tune crystallinity and shape of PUNNC for enhanced NIR-II responsive photothermal conversion efficiency and accelerated acid-induced dissolution for improved ·OH generation. Such 9T-PUNNC enable a combined chemodynamic-photothermal treatment to provide superior therapeutic efficacy due to their highly synergistic effect.

Exogenously Triggered Nanozyme for Real-Time Magnetic Resonance Imaging-Guided Synergistic Cascade Tumor Therapy.

The uncontrolled treatment process and high concentration of intracellular glutathione compromise the therapeutic efficacies of chemodynamic therapy (CDT). Here, iron oxide nanocrystals embedded in N-doped carbon nanosheets (IONCNs) are designed as a near-infrared light-triggered nanozyme for synergistic cascade tumor therapy. The IONCNs can absorb and convert 980 nm light to local heat, which induces the dissolution of iron oxide for generating Fe2+/Fe3+ in a weak acid environment, apart from thermal ablation of cancer cells. The formed Fe2+ takes on the active site for the Fenton reaction. The formed Fe3+ acts as glutathione peroxidase to magnify oxidative stress, improving the antitumor performance. The IONCNs can be used to visually track the treatment process via magnetic resonance imaging. Such IONCNs demonstrate great potential as an exogenously triggered nanozyme via an integrated cascade reaction for imaging-guided synergistic cancer therapy.

Ultrasmall Cu Nanocrystals Dispersed in Nitrogen-Doped Carbon as Highly Efficient Catalysts for CO2 Electroreduction.

The electroreduction of carbon dioxide (CO2) to a liquid product is a viable method for establishing an artificial carbon cycle. Unfortunately, most electrocatalysts' low efficiency and instability prevent them from being used in practical applications. In the current study, we developed ultrasmall Cu nanocrystals embedded in nitrogen-doped carbon nanosheets (Cu/NC-NSs) for selective CO2 electroreduction by adjusting the potential. Cu/NC-NSs had 43.7 and 63.5% Faradaic efficiencies for the synthesis of ethanol and formate with applied potentials of -0.37 and -0.77 V vs reversible hydrogen electrode (RHE) using a flow cell architecture, respectively. Moreover, these Cu/NC-NSs show a steady catalytic performance up to 16 h. Density functional theory (DFT) calculations were performed to investigate the reaction mechanism. Furthermore, the synergistic effect formed by nitrogen-doped carbon and highly dispersed copper atoms led to their excellent performance in CO2 electroreduction.

Hollow Cuprous Oxide@Nitrogen-Doped Carbon Nanocapsules for Cascade Chemodynamic Therapy.

Cuprous-based nanozymes have demonstrated great potential for cascade chemodynamic therapy (CDT) due to their higher catalytic efficiency and simple reaction conditions. Here, hollow cuprous oxide@nitrogen-doped carbon (HCONC) dual-shell structures are designed as nanozymes for CDT oncotherapy. This HCONC with a size distribution of 130 nm is synthesized by a one-step hydrothermal method using cupric nitrate and dimethyl formamide as precursors. The thin-layer carbon (1.88 nm) of HCONC enhances the water-stability and reduces the systemic toxicity of cuprous oxide nanocrystals. The dissolved Cu+ of HCONC in acid solution induces a Fenton-like reaction and exhibits a fast reaction rate for catalyzing H2 O2 into highly toxic hydroxyl radicals (·OH). Meanwhile, the formed Cu+ consumes oversaturated glutathione (GSH) to avoid its destruction of ROS at the intracellular level. In general, both cellular and animal experiments show that HCONC demonstrates excellent antitumor ability without causing significant systemic toxicity, which may present tremendous potential for clinical cancer therapy.

In situ immobilization of silver nanocrystals in carbon nanoparticles for intracellular fluorescence imaging and hydroxyl radicals detection.

Silver nanoparticles (Ag NPs) have attracted extensive research interest in bioimaging and biosensing due to their unique surface plasmon resonance. However, the potential aggregation and security anxiety of Ag NPs hinder their further application in biomedical field due to their high surface energy and the possible ionization. Here, binary heterogeneous nanocomplexes constructed from silver nanoparticles and carbon nanomaterials (termed as C-Ag NPs) were reported. The C-Ag NPs with multiple yolk structure were synthesized via a one-step solvothermal route using toluene as carbon precursor and dispersant. The hydrophilic functional groups on the carbon layer endowed the C-Ag NPs excellent chemical stability and water-dispersity. Results showed that C-Ag NPs demonstrated excellent safety profile and excellent biocompatibility, which could be used as an intracellular imaging agent. Moreover, the C-Ag NPs responded specifically to hydroxyl radicals and were expected to serve as a flexible sensor to efficiently detect diseases related to the expression of hydroxyl radicals in the future.

NIR-II Responsive Hollow Magnetite Nanoclusters for Targeted Magnetic Resonance Imaging-Guided Photothermal/Chemo-Therapy and Chemodynamic Therapy.

Phototherapy in the second near-IR (1000-1700 nm, NIR-II) window has achieved much progress because of its high efficiency and relatively minor side effects. In this paper, a new NIR-II responsive hollow magnetite nanocluster (HMNC) for targeted and imaging-guided cancer therapy is reported. The HMNC not only provides a hollow cavity for drug loading but also serves as a contrast agent for tumor-targeted magnetic resonance imaging. The acid-induced dissolution of the HMNCs can trigger a pH-responsive drug release for chemotherapy and catalyze the hydroxyl radical (·OH) formation from the decomposition of hydrogen peroxide for chemodynamic therapy. Moreover, the HMNCs can adsorb and convert NIR-II light into local heat (photothermal conversion efficacy: 36.3%), which can accelerate drug release and enhance the synergistic effect of chemo-photothermal therapy. The HMNCs show great potential as a versatile nanoplatform for targeted imaging-guided trimodal cancer therapy.

Phase solubility diagrams and energy surface calculations support the solubility enhancement with low hygroscopicity of Bergenin: 4-Aminobenzamide (1: 1) cocrystal.

Herein, we reported a new bergenin: 4-aminobenzamide (BGN-4AM) cocrystal with significantly enhanced solubility and low hygroscopicity probed from two aspects such as phase solubility diagrams and theoretical calculations. Compared with anhydrous BGN, BGN-4AM solubilities in water and different buffer solutions (pH = 1.2, 4.5, 6.8) increase significantly. It is noted that BGN-4AM solubility in pH = 6.8 buffer solution presents 32.7 times higher than anhydrous BGN. Interestingly, BGN-4AM (0.31 ± 0.07%) showcases lower hygroscopicity than anhydrous BGN (9.31 ± 0.16%). The predicted and experimental solubilities agree with each other when considering solubility product (Ksp) and solution binding constant (K11) in phase solubility diagrams, indicating the solution complexes formation occurs. Further crystal surface-water interactions and Bravais, Friedel, Donnay-Harker (BFDH) analyses based on Density Functional Theory with dispersion correction (DFT-d) methods support the enhanced solubility. The water probe demonstrates an average interaction energy of -6.48 kcal/mol on the 002 plane of BGN-4AM, and only -5.47 kcal/mol on the 011 plane of BGN monohydrate. The lower lattice energy of BGN-4AM guarantees its lower hygroscopicity than BGN monohydrate. BGN-4AM with enhanced solubility and low hygroscopicity can be a potential candidate for further formulation development.

Graphitic Carbon Nitride Quantum Dots Embedded in Carbon Nanosheets for Near-Infrared Imaging-Guided Combined Photo-Chemotherapy.

Rational design of metal-free multifunctional therapeutic reagents offers great opportunities for cancer treatment in the clinic. Here, graphitic carbon nitride (g-C3N4) quantum dots embedded in carbon nanosheets (CNQD-CN) are in situ prepared via a one-pot hydrothermal approach with formamide as carbon and nitrogen source. The CNQD-CN not only serves as an excellent near-infrared (NIR) fluorescent marker but also acts as a pH-responsive nanocarrier. Moreover, the CNQD-CN possesses both light-to-heat conversion and singlet oxygen generation capabilities under a single NIR excitation wavelength. Further investigations show that systemic delivery of doxorubicin (DOX) using the multifunctional CNQD-CN nanocarrier under NIR irradiation was highly effective to cause cancer cell apoptosis in vitro and inhibit tumor growth in vivo. CNQD-CN represents a multifunctional therapeutic platform for synchronous cancer imaging and treatment through the synergistic effect of phototherapy and chemotherapy.

In vivo deep-brain blood flow speed measurement through third-harmonic generation imaging excited at the 1700-nm window.

Measurement of the hemodynamic physical parameter blood flow speed in the brain in vivo is key to understanding brain physiology and pathology. 2-photon fluorescence microscopy with single blood vessel resolution is typically used, which necessitates injection of toxic fluorescent dyes. Here we demonstrate a label-free nonlinear optical technique, third-harmonic generation microscopy excited at the 1700-nm window, that is promising for such measurement. Using a simple femtosecond laser system based on soliton self-frequency shift, we can measure blood flow speed through the whole cortical grey matter, even down to the white matter layer. Together with 3-photon fluorescence microscopy, we further demonstrate that the blood vessel walls generate strong THG signals, and that plasma and circulating blood cells are mutually exclusive in space. This technique can be readily applied to brain research.

Direct carbonization of organic solvents toward graphene quantum dots.

The bottom-up synthesis of graphene quantum dots (GQDs) using solvothermal methods has attracted considerable attention because of their fewer defects and controllable size/morphology. However, the influence of organic solvents on the preparation of GQDs is still unknown. Herein, a systematic study on the carbonization of organic solvents toward GQDs is reported. The results show that organic solvents with the double bond or benzene ring or double hydrophilic groups could be directly decomposed into GQDs without the addition of catalysts or molecular precursors. The as-synthesized GQDs demonstrate ultra-small size distribution, high stability, tunable excitation wavelength and upconverted fluorescence. Both hematological and histopathological analyses show that the as-synthesized GQDs demonstrate a very good safety profile and excellent biocompatibility. The versatility of this synthesis strategy offers easy control of the surface group, composition, and optical properties of GQDs at the molecular level.