Smart nanozymes coupled with dynamic magnet field and laser exposures for cancer therapy.

Developing nanozymes for cancer therapy has attracted great attention from researchers. However, enzymes-loaded magnetic particles triggered by both a low-frequency vibrating magnetic field (VMF) and laser for inhibiting tumor growth have never been reported. Herein, we developed a magnetic nanozyme with 3D flower-like nanostructures for cancer therapy. Specifically, the flower-like nanozymes exposed to a VMF could efficiently damage the mitochondrial membrane and cell structure, and inhibit tumor growth through magneto-mechanical force. In parallel, magnetic nanozymes in a weak acid environment containing glucose could generate abundant hydrogen peroxide through glucose oxidase-catalyzed oxidation of glucose, and further significantly promote the Fenton reaction. Interestingly, both glucose oxidase- and Fenton-based catalytic reactions were significantly promoted by the VMF exposure. Flower-like magnetic nanospheres upon a near-infrared laser irradiation could also damage cancer cells and tumor tissues through photothermal effect. The cell-killing efficiency of magnetic nanozymes triggered by the VMF or laser significantly increased in comparison with that of nanozymes without exposures. Mouse tumors grown after injection with magnetic nanozymes was inhibited in a significant way or the tumors disappeared after exposure to a VMF and laser due to the synergistic effect of four major stimuli, viz., magneto-mechanical force, photothermal conversion, improved Fenton reaction, and intratumoral glucose consumption-based starvation effect. This is a great platform that may be suitable for treating many solid tumors.

Mito-Specific Nutri-Hijacker Synergizing Mitochondrial Metabolism and Glycolysis Intervention for Enhanced Antitumor Bioenergetic Therapy.

Metabolic rewiring, a dynamic metabolic phenotype switch, confers that tumors exist and proliferate after fitness (or preadaptation) in harsh environmental conditions. Glycolysis deprivation was considered to be a tumor's metabolic Achilles heel. However, metabolic configuration can flexibly retune the mitochondrial metabolic ability when glycolysis is scared, potentially resulting in more aggressive clones. To address the challenge of mitochondrial reprogramming, an antiglycolytic nanoparticle (GRPP NP) containing a novel mitochondrial-targeted reactive oxygen species (ROS) generator (diIR780) was prepared to hijack glucose and regulate mitochondria, thus completely eliminating tumorigenic energy sources. In this process, GRPP NPs@diIR780 can catalyze endogenous glucose, leading to significantly suppressed glycolysis. Moreover, diIR780 can be released and selectively accumulated around mitochondria to generate toxic ROS. These combined effects, in turn, can hamper mitochondrial metabolism pathways, which are crucial for driving tumor progression. This synchronous intervention strategy enables utter devastation of metabolic rewiring, providing a promising regiment to eradicate tumor lesions without recurrence.

Research on modification and noise reduction optimization of Electric Multiple Units traction gear under multiple working conditions.

The vibration and radiation noise characteristics of the gear transmission system are different under different traction conditions, and the gear modification optimization scheme based on a single working condition is not suitable for the operating environment under all working conditions. To modify the traction gear of a high-speed EMU, an optimized design scheme for noise reduction under multiple working conditions is proposed. A modification plan of the tooth direction in conjunction with the tooth shape was devised using a parametric model of the EMU's traction gear transmission system. The radiation noise of the gear transmission system after modification was solved using the acoustic boundary element method under different working conditions. A gear noise prediction model based on the random forest was proposed, and a gear modification parameter combination was constructed to minimize radiation noise. Then, the optimal design scheme of multi-condition modification combination parameters is obtained with the weight of the running time and acoustic contribution under different working conditions. The grey correlation degree evaluation model is established to verify that the multi-condition modification optimization design method can make the traction gear of EMU obtain satisfactory transmission performance and noise reduction effect under different working conditions.

Dry-Spinning of Artificial Spider Silk Ribbons From Regenerated Natural Spidroin in an Organic Medium.

Natural spider silks with striking performances achieve extensive investigations. Nonetheless, a lack of consensus over the mechanism of the natural spinning hinders the development of artificial spinning methods where the regenerated spider silks generally show poor performances compared with the natural fibers. As is known, the Plateau-Rayleigh instability tends to break solution column into droplets and is considered a main challenge during fiber-spinning. Here in this study, by harnessing the viscoelastic properties of the regenerated spidroin dope solution via organic salt-zinc acetate (ZA), this outcome can be avoided, and dry-spinning of long and mechanically robust regenerated spider silk ribbons can be successfully realized. The as-obtained dry-spun spider silk ribbons show an enhanced modulus up to 14 ± 4 GPa and a toughness of ≈51 ± 9 MJ m-3 after the post-stretching treatment, which is even better than that of the pristine spider silk fibers. This facile and flexible strategy enriches the spinning methodologies which bypass the bottleneck of precisely mimicking the complex natural environment of the glands in spiders, shining a light to the spider-silk-based textile industrial applications.

Synthesis and Antibacterial Activity Evaluation of Imidazole Derivatives Containing 6-Methylpyridine Moiety.

A series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4-yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles (15a-t and 16a-f) were synthesized and their antibacterial activities were evaluated. More than half of the compounds showed moderate or strong antibacterial activity. Among them, compounds 15t (MIC=1-2 µg/mL) and 16d (MIC=0.5 µg/mL) showed the strongest antibacterial activities. Notably, compound 16d did not exhibit cytotoxicity in HepG2 cells and did not show hemolysis like the positive control compound Gatifloxacin. The results suggest that compound 16d should be further investigated as a candidate antibacterial agent.

A painless and flexible bi-directional blood glucose-regulating system inspired by an inverter air conditioner.

Pursuing painless and flexible blood glucose regulation has been a century-long arduous mission. The current therapeutic systems can only regulate blood glucose unidirectionally (reduce), and the adjustment range is large, which is prone to the risk of hypoglycemia. Herein, inspired by the temperature fluctuation range controlled by the inverter air conditioner, we report a new bi-directional blood glucose-regulating drug delivery system (BDRS) consisting of glucose-loaded pressure-responsive nano-vesicles (Glu@PRNV), insulin-loaded black phosphorus nanosheets (Insulin@BPNs), hydrogel, and a painless blood sugar monitor patch. At first, BDRS could monitor blood glucose in real-time through visible color changes. Afterward, according to different requirements, BDRS could release glucose with the guidance of external pressure, or supplement insulin under near-infrared (NIR) irradiation, through which, the blood glucose level of diabetics could be accurately accommodated within a reasonable fluctuation range, thus minifying the likelihood of sudden hyperglycemia or hypoglycemia. Collectively, the supply-demand balance of blood glucose could be maintained via this real-time bi-directional drug delivery system, thereby improving the quality of life of diabetics. We have also verified the universality of this technique through a similar bi-directional sleep regulation.

Synergistic enhancement on flexible solid-state supercapacitor based on redox-active Fe3+ions/natural spidroin modified vertically aligned carbon nanotube arrays.

The conductive skeleton and aligned carbon nanotube array (CNTA) structure can greatly shorten the ion transfer path and promote the charge transfer speed, which makes the CNTA an ideal electrode material for energy storage application. However, poor mechanical stability and low specific capacitance greatly impede its practical utilization. Here, we introduce a promising flexible electrode material based on the natural spider silk protein (SSP) modified CNTA(SSP/CNTA) with improved hydrophilicity and mechanical flexibility. The redox-active Fe3+doped SSP/CNTA flexible solid-state supercapacitor (FSSC) device with superior energy storage performance was assembled in a symmetric 'sandwich-type' structure. The synergetic interaction between Fe3+ions and the SSP are proved to greatly enhance the electrochemical performance especially the long-term cyclic stability. The Fe3+doped SSP/CNTA FSSCs device achieves an ultra-high volumetric capacitance of 4.92 F cm-3at a sweep speed of 1 mV s-1. Meanwhile it exhibited an excellent cycling stability with an increased capacitance by 10% after 10 000 charge-discharge cycles. As a control, a Fe3+doped CNTA composite device without SSP will lose over 74% of the capacitance after 10 000 cycles. The energy storage mechanism analysis confirms the dominated capacitive behavior of the device, which explained a considerable power density and rate performance. Our method thus provides a promising strategy to build up highly-efficient redox-enhanced FSSCs for next generation of wearable and implantable electronics.

Photoresponsive porous ZnO-based broad-spectrum venom first-aid treatment.

A venomous snakebite is an emergency. However, antivenoms are rare and very similar, difficult to produce and preserve, and almost impossible to be used for emergency treatment. Therefore, it would be of great significance to develop convenient, efficient and broad-spectrum snake venom neutralizing nano-materials. In this study, inspired by boiled eggs, a new concept based on a ZnO complex (ZC) for the treatment of snake venoms is proposed. In vitro and in vivo experiments proved that ZC could widely adsorb biological (including snake) venoms and effectively reduce the concentration of toxic protein in the blood. More importantly, ZC could realize photothermal conversion under the stimulation of near-infrared (NIR) irradiation, resulting in protein hydrolyzation of venoms, thereby fundamentally prolonging survival time. In addition, ZC not only showed good biocompatibility, but also could inhibit bacterial reproduction, alleviate inflammation, and contribute to the healing of open wounds caused by biological venoms.

[Effect of Valeriana jatamansi extract on fecal UPLC-MS/MS metabolomics in rats with diarrheal irritable bowel syndrome].

The purpose of this study was to understand the pharmacodynamic effect of Valeriana jatamansi extract in diarrhea predominant irritable bowel syndrome(IBS-D) rat model induced by maternal separation combined with three kinds of stress, and observe the changes of endogenous metabolites in feces after intervention to find potential biomarkers and related metabolic pathways. The animal model of IBS-D was established by maternal separation combined with restraint, ice swimming and tail clamping. The therapeutic effect of each dose group of V. jatamansi extract was evaluated in terms of abdominal withdrawal reflex pressure threshold, fecal water content and immobility time of forced swimming test. In addition, rat feces were collected for detection of metabolic profiles of small molecular metabolites with UPLC-LTQ-Orbitrap MS platform, so as to find the biomarkers of differential metabolism with multivariate statistical analysis methods such as principal component analysis(PCA) and orthogon partial least squares discrimination analysis(OPLS-DA). The results showed that as compared with the normal group, the threshold of abdominal withdrawal reflex pressure was decreased, the fecal water content was increased, and the immobility time of forced swimming test was prolonged in the model group. The results of fecal metabonomics showed that the levels of 39 metabolites were down-regulated and those of 37 metabolites were up-re-gulated. Further analysis showed that these metabolites were related to bile acid metabolism, unsaturated fatty acid metabolism, amino acid metabolism, ceramide metabolism and other metabolic pathways. This study proved that the extract of V. jatamansi had definite pharmacodynamic effect on IBS-D model rats, and the mechanism was discussed from the perspective of fecal metabonomics.

A multi-effective and long-acting immunotherapy through one single hydrogel based injection.

A dual-effective (photothermal and immune) therapy employing gold nanorods (AuNRs) with a drug (two macrophage migration inhibitory factor (MIF) inhibitors) sustained release hydrogel was designed in this paper. The subsequent cellular and animal studies demonstrated that the proposed therapy can not only inhibit the proliferation, migration, and recurrence of cancer cells, but also improve the immune function (increase the infiltration of CD8+ killer T cells in tumors) without the traditional multiple injections of expensive immune drugs.

An accurate and dual-effective body slimming method through a soluble microneedle patch with variable temperature.

Obesity is a chronic and recurrent disease with potential risks. Traditional weight-loss methods (like exercises, surgeries, oral drugs, etc.) have shown different side effects. In this experiment, the microneedle (MN) patch was selected as the drug carrier of the weight-loss drug Rosiglitazone (Rosi). Besides, melanin was added to enhance the photo-thermal effect and accelerate the release of drugs to the target fat region under near-infrared (NIR) light. Afterwards, with exterior cold stimulation, the significant and accurate effect of body slimming could be achieved. This combination of soluble MN patches and variable temperatures provides an attractive nonsurgical method for future accurate body slimming management.

Banana Peel-Derived Dendrite-Shaped Au Nanomaterials with Dual Inhibition Toward Tumor Growth and Migration.

PURPOSE: In order to prepare functional Au nanoparticles with low toxicity and high antitumor properties, we have used fruit waste (banana peel) to synthesize a new dendrite-shaped gold nanoparticle and used it for the treatment of tumors. METHODS: Dendrite-shaped gold nanoparticle (Au-dendrite) was synthesized through a facile hydrothermal process. The banana peel was used as both the reducing agent and the protective agent for reducing chloroauric acid to obtain Au-dendrite. The safety assessment of the Au-dendrite was conducted by H&E staining of the mouse's eyelid skin and CCK-8 assay. The antitumor effects were evaluated through in vitro tumor cytotoxicity experiments and in vivo treatment of animal tumors. RESULTS: In this work, a new type of gold nanomaterial (Au-dendrite) was synthesized by using a common agricultural waste (banana peel) through a facile hydrothermal process without any extra chemical reducing agent or protective agent. Subsequent experiments showed that, compared with some classical Au nanomaterials, the as-synthesized gold nanocomposites have superior biocompatibility and impressive characteristics of dual inhibition toward tumor growth and migration. CONCLUSION: We successfully synthesized a dendrite-shaped gold nanocomposite which was derived from a common agricultural waste (banana peel). A facile and environmentally friendly synthetic process was proposed accordingly without regular chemical additives. The as-prepared Au-dendrite nanocomposites not only had better biocompatibility than some classical gold nanoparticles but also exhibited unique advantages in tumor inhibition.

Porous ZnO modified silk sutures with dual light defined antibacterial, healing promotion and controlled self-degradation capabilities.

Current sutures have disadvantages such as poor antibacterial activities, low healing effects, and a lack of self-degradation ability. To solve these problems, here a biocompatible and dual light (yellow and NIR light) responsive porous ZnO (PZ) was synthesized to modify silk thread to improve the healing rate, antibacterial activities and controlled self-degradation speed simultaneously. The prepared silk thread was characterized by using scanning electron microscopy (SEM) and X-ray diffractometry (XRD). Besides, the antibacterial activity, degradation, dual light responsive capability and cytocompatibility of the sample were evaluated. The obtained data strongly encourage the application of this silk thread for wound treatment. Furthermore, in vivo evaluation in mice revealed that the silk thread reduced surgical-site infection and enhanced wound healing. Therefore, this silk thread shows potential for application in wound treatment clinically.

Dbo/Henji Modulates Synaptic dPAK to Gate Glutamate Receptor Abundance and Postsynaptic Response.

In response to environmental and physiological changes, the synapse manifests plasticity while simultaneously maintains homeostasis. Here, we analyzed mutant synapses of henji, also known as dbo, at the Drosophila neuromuscular junction (NMJ). In henji mutants, NMJ growth is defective with appearance of satellite boutons. Transmission electron microscopy analysis indicates that the synaptic membrane region is expanded. The postsynaptic density (PSD) houses glutamate receptors GluRIIA and GluRIIB, which have distinct transmission properties. In henji mutants, GluRIIA abundance is upregulated but that of GluRIIB is not. Electrophysiological results also support a GluR compositional shift towards a higher IIA/IIB ratio at henji NMJs. Strikingly, dPAK, a positive regulator for GluRIIA synaptic localization, accumulates at the henji PSD. Reducing the dpak gene dosage suppresses satellite boutons and GluRIIA accumulation at henji NMJs. In addition, dPAK associated with Henji through the Kelch repeats which is the domain essential for Henji localization and function at postsynapses. We propose that Henji acts at postsynapses to restrict both presynaptic bouton growth and postsynaptic GluRIIA abundance by modulating dPAK.

Neurofibromin mediates FAK signaling in confining synapse growth at Drosophila neuromuscular junctions.

Neurofibromatosis type I (NF1), caused by the mutation in the NF1 gene, is characterized by multiple pathological symptoms. Importantly, ~50% of NF1 patients also suffer learning difficulty. Although downstream pathways are well studied, regulation of the NF1-encoded neurofibromin protein is less clear. Here, we focused on the pathophysiology of Drosophila NF1 mutants in synaptic growth at neuromuscular junctions. Our analysis suggests that the Drosophila neurofibromin protein NF1 is required to constrain synaptic growth and transmission. NF1 functions downstream of the Drosophila focal adhesion kinase (FAK) Fak56 and physically interacts with Fak56. The N-terminal region of NF1 mediates the interaction with Fak56 and is required for the signaling activity and presynaptic localization of NF1. In presynapses, NF1 acts via the cAMP pathway, but independent of its GAP activity, to restrain synaptic growth. Thus, presynaptic FAK signaling may be disrupted, causing abnormal synaptic growth and transmission in the NF1 genetic disorder.

Activity-dependent retrograde laminin A signaling regulates synapse growth at Drosophila neuromuscular junctions.

Retrograde signals induced by synaptic activities are derived from postsynaptic cells to potentiate presynaptic properties, such as cytoskeletal dynamics, gene expression, and synaptic growth. However, it is not known whether activity-dependent retrograde signals can also depotentiate synaptic properties. Here we report that laminin A (LanA) functions as a retrograde signal to suppress synapse growth at Drosophila neuromuscular junctions (NMJs). The presynaptic integrin pathway consists of the integrin subunit ßν and focal adhesion kinase 56 (Fak56), both of which are required to suppress crawling activity-dependent NMJ growth. LanA protein is localized in the synaptic cleft and only muscle-derived LanA is functional in modulating NMJ growth. The LanA level at NMJs is inversely correlated with NMJ size and regulated by larval crawling activity, synapse excitability, postsynaptic response, and anterograde Wnt/Wingless signaling, all of which modulate NMJ growth through LanA and ßν. Our data indicate that synaptic activities down-regulate levels of the retrograde signal LanA to promote NMJ growth.