Multistage-Responsive Dual-Enzyme Nanocascades for Synergistic Radiosensitization-Starvation Cancer Therapy.

Radiotherapy is a common cancer treatment approach in clinical practice, yet its efficacy has been restricted by tumor hypoxia. Nanomaterials-mediated systemic delivery of glucose oxidase (GOx) and catalase (CAT) or CAT-like nanoenzymes holds the potential to enhance tumor oxygenation. However, they face the challenge of intermediate (hydrogen peroxide [H2 O2 ]) escape during systemic circulation if the enzyme pair is not closely placed to largely decompose H2 O2 , leading to oxidative stress on normal tissues. In the present study, a oxygen-generating nanocascade, n(GOx-CAT)C7A , constructed by strategically placing an enzymatic cascade (GOx and CAT) within a polymeric coating rich in hexamethyleneimine (C7A) moieties, is reported. During blood circulation, C7A remains predominantly non-protonated , achieving prolonged blood circulation due to its low-fouling surface. Once n(GOx-CAT)C7A reaches the tumor site, the acidic tumor microenvironment (TME) induces protonation of C7A moieties, resulting in a positively charged surface for enhanced tumor transcytosis. Moreover, GOx and CAT are covalently conjugated into close spatial proximity (<10 nm) for effective H2 O2  elimination. As demonstrated by the in vivo results, n(GOx-CAT)C7A achieves effective tumor retention and oxygenation, potent radiosensitization and antitumor effects. Such a dual-enzyme nanocascade for smart O2  delivery holds great potential for enhancing the hypoxia-compromised cancer therapies.

2-Hydroxypropyl Group Linked Derivatives of Indole Azoles as Potential Multifunctional Antibacterial Candidates for Effectively Inhibiting the Activity of MRSA and Responding Inflammatory Factors.

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to escalating efforts to design and synthesize new structural agents with significant antimicrobial potential. A novel class of 2-hydroxypropyl group linked derivatives of indole azoles was developed as potential antibacterial agents. Bioactivity screening results demonstrated that metronidazole-modified indole derivative 4 a had excellent antibacterial capacity against MRSA (MIC=6 µM), which was about 4 times that of norfloxacin (MIC=25 µM). Highly active hybrid 4 a did not cause obvious drug-resistance in MRSA after multiple generations (15 passage operations). Compound 4 a showed low toxicity to normal mammalian cells (RAW 264.7). Molecular docking and molecular electrostatic potential (MEP) surface studies were used to map hydrogen bond interactions and the electron distribution in the highly active compounds. In addition, the preliminary exploration of the antibacterial mechanism revealed that the active molecule 4 a could infiltrate the membrane of MRSA and insert into MRSA DNA to prevent its replication, thus activating strong inhibition of the bacteria. Furthermore, highly active derivative 4 a could better respond to inflammatory factors (IL-6, IL-10, TNF-α and PGE-2), and it is less likely to cause inflammatory complications, hence diversifying the functions of antibacterial candidate molecules. These findings effectively indicate the potential of the bioactive hybrid 4 a as a multifunctional anti-MRSA agent. Further exploration of the development of antimicrobials combining these kinds of 2-hydroxypropyl group linked indole derivatives is of great value.

Comprehensive assessment of intelligent unmanned vehicle techniques in pesticide application: A case study in pear orchard.

The intelligent pesticide application techniques in orchards have grown rapidly worldwide due to the decrease in agricultural populations and the increase in labor costs. However, whether and how intelligent pesticide application techniques are better than conventional pesticide application remains unclear. Here, we evaluated the performance of the unmanned aircraft vehicle (UAV) and unmanned ground vehicle (UGV) on pesticide application, ecological environment protection, and human's health protection compared to conventional manual methods. We quantified characteristics from the aspects of working effectiveness, efficiency, environmental pollution, water saving and carbon dioxide reduction. The results showed that the UAV application has the advantages of a higher working efficiency and less environmental pollution and natural resource consumption compared to the UGV and conventional manual methods despite of its worse spray performance The UGV application techniques could improve spray performance at the cost of high environmental pollution. The conventional spray gun technique was unfriendly to environmental and resource protection although it showed a better spray performance. Thus, the balance of improving spray performance and controlling environmental pollution is the key to improve the performance of UAV and UGV technology in the future. The study could be useful in the development of intelligent pesticide application techniques and provide scientific support for the transition of intelligent management in orchards.

Potential antibacterial ethanol-bridged purine azole hybrids as dual-targeting inhibitors of MRSA.

A new class of antibacterial ethanol-bridged purine azole hybrids as potential dual-targeting inhibitors was developed. Bioactivity evaluation showed that some of the target compounds had prominent antibacterial activity against the tested bacteria, notably, metronidazole hybrid 3a displayed significant inhibitory activity against MRSA (MIC = 6 µM), and had no obvious toxicity on normal mammalian cells (RAW 264.7). In addition, compound 3a also did not induce drug resistance of MRSA obviously, even after fifteen passages. Molecular modeling studies showed that the highly active molecule 3a could insert into the base pairs of topoisomerase IA-DNA as well as topoisomerase IV-DNA through hydrogen bonding. Furthermore, a preliminary study on the antibacterial mechanism revealed that the active molecule 3a could rupture the bacterial membrane of MRSA and insert into MRSA DNA to block its replication, thus possibly exhibiting strong antibacterial activity. These results strongly indicated that the highly active hybrid 3a could be used as a potential dual-targeting inhibitor of MRSA for further development of valuable antimicrobials.

Novel chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids as potential antibacterial repressors against methicillin-resistant Staphylococcus aureus.

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to a growing effort to design and synthesize novel structural candidates of chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids with outstanding bacteriostatic potential. Bioactivity screening showed that hybrid 5i, which was modified with methoxybenzene, exerted a significant inhibitory activity against MRSA (MIC = 0.004 mM), which was 6 times better than the anti-MRSA activity of the reference drug norfloxacin (MIC = 0.025 mM). Compound 5i neither conferred apparent resistance onto MRSA strains even after multiple passages nor triggered evident toxicity to human hepatocyte LO2 cells and normal mammalian cells (RAW 264.7). Molecular docking showed that highly active molecule 5i might bind to DNA gyrase by forming stable hydrogen bonds. In addition, molecular electrostatic potential surfaces were developed to explain the high antibacterial activity of the target compounds. Furthermore, preliminary mechanism studies suggested that hybrid 5i could disrupt the bacterial membrane of MRSA and insert itself into MRSA DNA to impede its replication, thus possibly becoming a potential antibacterial repressor against MRSA.

Butyrylcholinesterase nanodepots with enhanced prophylactic and therapeutic performance for acute organophosphorus poisoning management.

Acute organophosphorus pesticide poisoning (AOPP) is a worldwide health concern that has threatened human lives for decades, which attacks acetylcholinesterase (AChE) and causes nervous system disorders. Classical treatment options are associated with short in vivo half-life and side effects. As a potential alternative, delivery of mammalian-derived butyrylcholinesterase (BChE) offers a cost-effective way to block organophosphorus attack on acetylcholinesterase, a key enzyme in the neurotransmitter cycle. Yet the use of exotic BChE as a prophylactic or therapeutic agent is compromised by short plasma residence, immune response and unfavorable biodistribution. To overcome these obstacles, BChE nanodepots (nBChE) composed of a BChE core/polymorpholine shell structure were prepared via in situ polymerization, which showed enhanced stability, prolonged plasma circulation, attenuated antigenicity and reduced accumulation in non-targeted tissues. In vivo administration of nBChE pre- or post-organophosphorus exposure in a BALB/C mouse model resulted in potent prophylactic and therapeutic efficiency. To our knowledge, this is the first systematic delivery of non-human BChE to tackle AOPP. In addition, this work also opens up a new avenue for real applications in both research and clinical settings to cope with acute intoxication-related diseases.