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The combination of gene therapy with chemotherapeutics provides an efficacious strategy for enhanced tumor therapy. RNA-cleaving DNAzyme has been recognized as a promising gene-silencing tool, while its combination with chemotherapeutic drugs has been limited by the lack of an effective codelivery system to allow sufficient intracellular DNAzyme activation, which requires specific metal ions as a cofactor. Here, a self-activatable DNAzyme/drug core–shell codelivery system is fabricated to combat triple-negative breast cancer (TNBC). The hydrophobic chemotherapeutic, rapamycin (RAP), is self-assembled into the pure drug nanocore, and the metal–organic framework (MOF) shell based on coordination between Mn2+ and tannic acid (TA) is coated on the surface to coload an autophagy-inhibiting DNAzyme. The nanosystem efficiently delivers the payloads into tumor cells, and upon endocytosis, the MOF shell is disintegrated to release the therapeutics in response to an acidic endo/lysosome environment and intracellular glutathione (GSH). Notably, the coreleased Mn2+ serves as the cofactor of DNAzyme for effective self-activation, which suppresses the expression of Beclin 1 protein, the key initiator of autophagy, resulting in a significantly strengthened antitumor effect of RAP. Using tumor-bearing mouse models, the nanosystem could passively accumulate into the tumor tissue, impose potent gene-silencing efficacy, and thus sensitize chemotherapy to inhibit tumor growth upon intravenous administration, providing opportunities for combined gene-drug TNBC therapy.

The present work investigated the phenolic profiles (including nonanthocyanin and anthocyanin phenolics), antioxidant activities, and neuroprotective potential of mulberry fruit (MF) (Morus atropurpurea Roxb.) grown in China at different ripening stages. High-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) was used to identify and quantify the phenolic compounds. The antioxidant capacity, total phenolic content (TPC), total flavonoid content (TFC), and total monomeric anthocyanin content (TAC) were determined using spectrophotometric methods. The neuroprotective effects of MFs at different ripening stages were investigated using Aβ -treated PC12 cells as the cellular model of Alzheimer's disease. Of the 19 phenolic compounds characterized from the MF extracts, the contents of rutin and anthocyanins increased and that of chlorogenic acid decreased significantly with maturity. At the fully ripened stage, MF extracts showed the highest amounts of TPC (11.23 mg gallic acid equivalents/g fresh weight), TFC (15.1 mg rutin equivalents/g fresh weight), and TAC (1177 mg cyanidin 3-O-glucoside equivalents/100 g fresh weight). Meanwhile, antioxidant activity of MF extracts at this stage was highest according to ABTS (an IC50 value of 4.11 μg/mL) and DPPH (an IC50 value of 10.08 μg/mL) assays. Cellular assays revealed increased cell viability in cells treated with the ripe MF extracts; compared with the control groups, the ripening fruits also increased the antioxidant enzyme levels in PC12 cells. Together, these results suggest that the antioxidant activities and neuroprotective properties of ripening MFs are related to the contents and types of phenolic compounds that are present in the fruits.

Physical exercise is effective in alleviating mental disorders by improving synaptic transmission; however, the link between body endurance training and neural adaptation has not yet been completely resolved. In this study, the authors investigated the role of RNA N6‐methyladenosine (m6A), an emerging epigenetic mechanism, in improved resilience against chronic restraint stress. A combination of molecular, behavioral, and in vivo recording data demonstrates exercise‐mediated restoration of m6A in the mouse medial prefrontal cortex, whose activity is potentiated to exert anxiolytic effects. Furthermore, it is revealed that hepatic biosynthesis of one methyl donor is necessary for exercise to improve brain RNA m6A to counteract environmental stress. This novel liver‐brain axis provides an explanation for brain network changes upon exercise training and provides new insights into the diagnosis and treatment of anxiety disorders.

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