Synthesis and radioprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives.

As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC-6 and HFL-1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)-induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)-induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5+ intestinal stem cells, lysozyme+ Paneth cells and Ki67+ transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase-9 and caspase-3, and upregulated the expression of Bcl-2, suggesting that it could prevent irradiation-induced intestinal damage through the p53-dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.

Design, synthesis, and neuroprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opened derivatives.

To develop anti-ischemic stroke drugs with higher blood-brain barrier (BBB) penetrating capability and neuroprotective activity, a series of hybrid compounds containing edaravone analogue and 3-n-butylphthalide (NBP) ring-opened derivatives were synthesized and biologically evaluated. Among them, compound 10a displayed the highest protective activity in SH-SY5Y cells against oxygen and glucose deprivation (OGD) and H2O2 insults. Experiment results indicated that 10a could inhibit platelet aggregation via the synergistic action of the edaravone analogue and NBP, and its oral administration protected the rats against ischemia/reperfusion-induced brain injury. Moreover, 10a effectively inhibited apoptosis and reduced oxidative stress in OGD-exposed cells. Further analysis suggested that 10a might alleviate oxidative damage in SH-SY5Y cells via the modulation of the Nrf2 pathway. Collectively, these findings demonstrate that 10a can emerge as a potential candidate drug for the treatment of ischemic stroke.

Preparation of co-Co3 O4 /carbon nanotube/carbon foam for glucose sensor.

Co-Co3 O4 /carbon nanotube/carbon foam (Co-Co3 O4 /CNT/CF) nanocomposites were prepared by soaking melamine foam into a solution of Co(NO3 )2 ·6H2 O, followed by calcination in N2 and air in sequence. The obtained Co-Co3 O4 /CNT/CF nanocomposites were characterized with scanning electron microscopy and cyclic voltammetry. It was found that Co3 O4 nanoparticles were grown on the external of CF successfully, while CNTs were grown on the surfaces of CF in a large amount, which further improved the electrical conductivity of the. The prepared Co-Co3 O4 /CNT/CF nanocomposites were then used to construct nonenzymatic sensor to detect glucose in alkaline solution. The sensor showed detection range from 1.2 µM to 2.29 mM with a detection limit of 0.4 µM (S/N =3) and a high sensitivity of 637.5 µA-1 cm-2 . The developed sensor also showed an instant response, favorable reproducibility, and high selectivity. The results attest that Co-Co3 O4 /CNT/CF composites have great potential in the development of nonenzymatic sensors for glucose.

Photothermophoretic Splitting of Gold Nanoparticles for Plasmonic Nanopores and Nanonets Sensing.

Optical processing of single plasmonic nanoparticles reinvents the way of high-density information storage, high-performance sensing, and high-definition displays. However, such laser-fabricated nanoplasmonics with well-defined hot spots remain elusive due to the diffraction limit of light. Here we show Au nanoparticle (NP) decorated nanopores can be facilely generated with photothermal splitting of single Au NPs embedded in a silica matrix. The extremely high local temperature induced by plasmonic heating renders gradients of the temperature and surface tension around the Au NP, which drives the nanoscale thermophoretic and Marangoni flow of molten Au/silica. As a result, a nanopore decorated with fragmented Au NPs is formed in the silica film, which presents much stronger surface-enhanced Raman scattering as compared to a single Au NP due to the emergence of hot spots. This strategy can be used to generate plasmonic nanopores of various sizes in the silicon nitride (SiNx) films, which further transforms into nanonets at ambient conditions via light-induced reconstruction of silicon nitride membrane. These nanonets can serve as a robust platform for single particle trapping and analysis.

Protective mechanism of a novel aminothiol compound on radiation-induced intestinal injury.

PURPOSE: With the development of nuclear technology and radiotherapy, the risk of radiation injury has been increasing. Therefore, it is important to find an effective radiation-protective agent. In this study, we designed and synthesized a novel compound called compound 8, of which the radioprotective effect and mechanism were studied. MATERIALS AND METHODS: Before being exposed to ionizing radiation, mice were pretreated with compound 8. The 30-day mortality assay, hematoxylin-eosin staining, and immunohistochemistry staining assay were performed to evaluate the anti-radiation effect of the compound 8. TUNEL and immunofluorescence assays were conducted to study the anti-radiation mechanism of compound 8. RESULTS: Compared to the IR + vehicle group, the 30-day survival rate of mice treated with 25 mg/kg of compound 8 was significantly improved after 8 Gy total body irradiation. In the morphological study of the small intestine, we found that compound 8 could maintain crypt-villus structures in the irradiated mice. Further immunohistochemical staining displayed that compound 8 could improve the survival of Lgr5+ cells, ki67+ cells, and lysozyme+ cells. The results of TUNEL and immunofluorescence assays showed that compound 8 could decrease the expression of apoptosis-related caspase-8/-9, γ-H2AX, Bax, and p53. CONCLUSIONS: These results indicate that compound 8 exerts its effects by maintaining structure and function of small intestine. It also reduces DNA damage, promotes crypt proliferation and differentiation. Moreover, it may enhance the anti-apoptotic ability of small intestinal tissue by inhibiting the activation of p53 and blocking the caspase cascade reaction. Compound 8 can protect the intestinal tract from post-radiation damage, it is thus a new and effective protective agent of radiation.

Single-Nanoparticle-Based Nanomachining for Fabrication of a Uniform Nanochannel Sensor.

The structure of nanomaterials and nanodevices determines their functionality and applications. A single uniform nanochannel with a high aspect ratio is an attractive structure due to its unique rigid structures, easy preparation, and diverse pore structures and it holds significant promising importance in fields such as nanopore sensing and nanomanufacturing. Although the metal-nanoparticle-assistant silicon etching technique can produce uniform nanochannels, however, the fabrication of single through nanochannels remains a challenge thus far. A simple and versatile strategy is developed that allows for the retention of individual gold nanoparticle on a substrate, enabling single-nanoparticle nanomachining. This method involves three steps: the formation of a carbon protective layer on individual nanoparticles via electron-beam irradiation, selective removal of unprotected nanoparticles using a corrosive agent, and subsequent elimination of the carbon layer. This enables the fabrication of a single submillimeter-long uniform through nanochannel in the silicon wafer, which can be employed for nanopore sensing and shape-based nanoparticle distinguishing. The developed method can also facilitate single-nanoparticle studies and nanomachining for a broad application in materials science, electronics, micro/nano-optics, and catalysis.

Identification of plasmon-driven nanoparticle-coalescence-dominated growth of gold nanoplates through nanopore sensing.

The fascinating phenomenon that plasmon excitation can convert isotropic silver nanospheres to anisotropic nanoprisms has already been developed into a general synthetic technique since the discovery in 2001. However, the mechanism governing the morphology conversion is described with different reaction processes. So far, the mechanism based on redox reactions dominated anisotropic growth by plasmon-produced hot carriers is widely accepted and developed. Here, we successfully achieved plasmon-driven high yield conversion of gold nanospheres into nanoplates with iodine as the inducer. To investigate the mechanism, nanopore sensing technology is established to statistically study the intermediate species at the single-nanoparticle level. Surprisingly, the morphology conversion is proved as a hot hole-controlled coalescence-dominated growth process. This work conclusively elucidates that a controllable plasmon-driven nanoparticle-coalescence mechanism could enable the production of well-defined anisotropic metal nanostructures and suggests that the nanopore sensing could be of general use for studying the growth process of nanomaterials.

Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL-003.

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.

Seed-mediated growth of high yield Au nanoplates with in situ generated Au clusters through galvanic replacement.

A photochemical method is used to grow Au nanoplates in high yield from in situ generated Au cluster seeds through the galvanic replacement reaction. The morphology of nanoplates can be further controllably tuned by adjusting the pH, and enhanced morphology determined non-linear optics performances are obtained.

Design, Synthesis, and Biological Evaluation of a Novel Aminothiol Compound as Potential Radioprotector.

The risk of radiation damage has increased with the rapid development of nuclear technology and radiotherapy. Hence, research on radioprotective agents is of utmost importance. In the present study, a novel aminothiol compound 12, containing a linear alkylamino backbone and three terminal thiols, was synthesized. Owing to the appropriate capped groups in the chains, it has an improved permeability and oral bioavailability compared to other radioprotective agents. Oral administration of compound 12 improved the survival of mice that received lethal doses of γ-irradiation. Experimental results demonstrated that compound 12 not only mitigated total body irradiation-induced hematopoietic injury by increasing the frequencies of hematopoietic stem and progenitor cells but also prevented abdominal irradiation-induced intestinal injury by increasing the survival of Lgr5+ intestinal cells, lysozyme+ Paneth cells, and Ki67+ cells. In addition, compound 12 decreased oxidative stress by upregulating the expression of Nrf2 and NQO1 and downregulating the expression of NOX1. Further, compound 12 inhibited γ-irradiation-induced DNA damage and alleviated G2/M phase arrest. Moreover, compound 12 decreased the levels of p53 and Bax and increased the level of Bcl-2, demonstrating that it may suppress radiation-induced apoptosis via the p53 pathway. These results indicate that compound 12 has the possibility of preventing radiation injury and can be a potential radioprotector for clinical applications.

Oral Codelivery of WR-1065 Using Curcumin-Linked ROS-Sensitive Nanoparticles for Synergistic Radioprotection.

Protecting the body from radiation damage is a huge medical challenge. Amifostine and curcumin are both effective radioprotectants, but their use has been greatly restricted due to various reasons including low bioavailability. Nanoscale drug delivery systems of poly(ethylene glycol)-poly(ε-caprolactone) copolymers can improve the bioavailability of drugs due to excellent biocompatibility, biodegradability, and long circulation characteristics. In this study, a new reactive oxygen species-sensitive nanocarrier fabricated by linking curcumin and thioketal to poly(ethylene glycol)-poly(ε-caprolactone) polymer was used for delivery of WR-1065 (the active ingredient of amifostine). The content of curcumin in this polymer was about 7.6%, and the drug loading of WR-1065 was 44%. The WR-1065-loaded nanoparticles (NPs) had an average size of 128.6 nm and uniform spherical morphology. These WR-1065-loaded NPs reduced the metabolism of curcumin and WR-1065 in the gastrointestinal tract and could be well absorbed by cells and distributed to multiple organs. Compared with a single drug, oral administration of WR-1065-loaded NPs demonstrated obvious radioprotective effects on the hematopoietic system and prevented intestinal injury. The 30-day survival rate after half-lethal dose (7.2 Gy) of total body irradiation was 100%. In general, WR-1065-loaded NPs improved the oral bioavailability of WR-1065 and curcumin. This multifunctional nanocarrier provides a possibility for combination therapy in treating ionizing radiation damage.

Development of ERK1/2 inhibitors as a therapeutic strategy for tumour with MAPK upstream target mutations.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates that play key roles in promoting cell survival and proliferation. Many inhibitors, acting on upstream of the ERK pathway, exhibit excellent antitumor activity. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be effective against cancers with altered MAPK upstream pathway and may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. In this review, we describe the mechanism and types of ERK1/2 inhibitors, summarise the current development status of small-molecule ERK1/2 inhibitors, including the preclinical data and clinical study progress, and discuss the future research directions for the application of ERK1/2 inhibitors.

Design and evaluation of pH-responsive hydrogel for oral delivery of amifostine and study on its radioprotective effects.

The purpose of this study was to develop a novel pH-sensitive hydrogel which was used to regulate the acute radiation syndrome (ARS). The hydrogel was fabricated by grafting polycaprolactone onto methacrylic acid copolymer (MAC-g-PCL). Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (1H NMR) confirmed the obtaining of MAC-g-PCL hydrogel. The hydrogel was pH-sensitive, at pH 1.2, it was compact hydrogel, but at pH7.4, it was dissolved solution. Its inner 3D morphology was observed by scanning electron microscope (SEM). Cell experiments indicated that the MAC-g-PCL hyrogel was out of cytotoxicity. The release profile of amifostine showed that small amount drug release in simulated gastric fluid (pH 1.2) and burst release in simulated intestinal fluid (pH 7.4). Thus, the pH-sensitive hydrogels could protect amifostine from enzymatic degradation in acidic stomach and deliver effectively in the intestine. The radioprotective efficacy was determined by peripheral complete blood parameters and 30-day survival study in mice acutely exposed to 4 Gy γ-ray total body irradiation. Results suggested that oral administration MAC-g-PCL/Ami before total body irradiation protected the mice from hematopoietic ARS and enhanced their survival. Furthermore, in vivo bio-distribution studies indicated that the drug could be sustained delivered at intestinal tract and entered the bloodstream. These results demonstrated that oral administration of amifostine hydrogel provided effective radioprotection to reduce the ARS injury.

Simple and Large-Scale Strategy to Prepare Flexible Graphene Tape Electrode.

A simple and large-scale strategy to prepare flexible graphene tape electrode (GTE) was proposed. The flexible GTE was prepared by a facile peeling method in which a piece of commercial graphite foil was first covered by a commercial acrylic transparent tape and then the transparent adhesive tape was quickly torn off from the graphite foil. Scanning electron microscopy results showed that some folded and wrinkled graphene layers stood up on the GTE surface to form three-dimensional (3D) porous graphene foam. The 3D porous flexible GTE was proposed as a novel supporting matrix to load Ni-Co nanoparticles (Ni-CoNPs) and glucose oxidase (GOD) as examples to test its applications for electrochemical glucose sensing. The Ni-CoNPs/GTE showed the linear range of 0.6 µM-0.26 mM and 1.360-5.464 mM with a detection limit of 0.16 µM. The GOD/AuNPs-CHIT/GTE had a linear range of 0.616-14.0 mM and a detection limit of 0.202 mM. These results were similar or superior to the printable electrodes by nanocarbon and electrodes modified with graphene, carbon nanotubes, or porous carbon materials, but the flexible GTE was more easier to prepare in large-scale and the 3D porous graphene foam were not easy to drop off from the tape because they were glued on acrylic transparent tape firmly. Therefore, the 3D porous flexible GTE should be promising candidates for electrochemical sensors and other electrochemical applications.

Smart Nanocomposites of Cu-Hemin Metal-Organic Frameworks for Electrochemical Glucose Biosensing.

Herein, a smart porous material, Cu-hemin metal-organic-frameworks (Cu-hemin MOFs), was synthesized via assembling of Cu2+ with hemin to load glucose oxidase (GOD) for electrochemical glucose biosensing for the first time. The formation of the Cu-hemin MOFs was verified by scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, N2 adsorption/desorption isotherms, UV-vis absorption spectroscopy, fluorescence spectroscopy, thermal analysis and electrochemical techniques. The results indicated that the Cu-hemin MOFs showed a ball-flower-like hollow cage structure with a large specific surface area and a large number of mesopores. A large number of GOD molecules could be successfully loaded in the pores of Cu-hemin MOFs to keep their bioactivity just like in a solution. The GOD/Cu-hemin MOFs exhibited both good performance toward oxygen reduction reaction via Cu-hemin MOFs and catalytic oxidation of glucose via GOD, superior to other GOD/MOFs and GOD/nanomaterials. Accordingly, the performance of GOD/Cu-hemin MOFs-based electrochemical glucose sensor was enhanced greatly, showing a wide linear range from 9.10 µM to 36.0 mM and a low detection limit of 2.73 µM. Moreover, the sensor showed satisfactory results in detection of glucose in human serum. This work provides a practical design of new electrochemical sensing platform based on MOFs and biomolecules.