Harnessing Nanochaperone-Mediated Autophagy for Selective Clearance of Pathogenic Tau Protein in Alzheimer's Disease.

Accumulation of pathological tau is a hallmark of Alzheimer's disease (AD), which correlates more closely with cognitive impairment than does the amyloid-ß (Aß) burden. Autophagy is a powerful process for the clearance of toxic proteins including aberrant tau. However, compromised autophagy is demonstrated in neurodegeneration including AD, and current autophagy inducers remain enormously challenging due to inability of restoring autophagy pathway and lack of targeting specificity. Here, pathogenic tau-specific autophagy based on customized nanochaperone is developed for AD treatment. In this strategy, the nanochaperone can selectively bind to pathogenic tau and maintain tau homeostasis, thereby ensuring microtubule stability which is important for autophagy pathway. Meanwhile, the bound pathogenic tau can be sequestered in autophagosomes by in situ autophagy activation of nanochaperone. Consequently, autophagosomes wrapping with pathogenic tau are able to be trafficked along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in the enhancement of autophagic flux and pathologic tau clearance. After treatment with this nanochaperone-mediated autophagy strategy, the tau burden, neuron damages, and cognitive deficits of AD mice are significantly alleviated in the brain. Therefore, this work represents a promising candidate for AD-targeted therapy and provides new insights into future design of anti-neurodegeneration drugs.

Root exudates influence rhizosphere fungi and thereby synergistically regulate Panax ginseng yield and quality.

Root exudates contain a complex array of primary and specialized metabolites that play important roles in plant growth due to their stimulatory and inhibitory activities that can select for specific microbes. In this study, we investigated the effects of different root exudate concentrations on the growth of ginseng (Panax ginseng C. A. Mey), ginsenoside levels, and soil fungal community composition and diversity. The results showed that low root exudate concentrations in the soil promoted ginseng rhizome biomass and ginsenoside levels (Rg1, Re, Rf, Rg2, Rb1, Ro, Rc, Rb2, Rb3, and Rd) in rhizomes. However, the rhizome biomass and ginsenoside levels gradually decreased with further increases in the root exudate concentration. ITS sequencing showed that low root exudate concentrations in the soil hardly altered the rhizosphere fungal community structure. High root exudate concentrations altered the structure, involving microecological imbalance, with reduced abundances of potentially beneficial fungi (such as Mortierella) and increased abundances of potentially pathogenic fungi (such as Fusarium). Correlation analysis showed that rhizome biomass and ginsenoside levels were significantly positively correlated with the abundances of potentially beneficial fungi, while the opposite was true for potentially pathogenic fungi. Overall, low root exudate concentrations promote the growth and development of ginseng; high root exudate concentrations lead to an imbalance in the rhizosphere fungal community of ginseng and reduce the plant's adaptability. This may be an important factor in the reduced ginseng yield and quality and soil sickness when ginseng is grown continuously.

Self-Assembly Nanochaperone with Tunable Hydrophilic-Hydrophobic Surface for Controlled Protein Refolding.

Nanochaperones (nChaps) have significant potential to inhibit protein aggregation and assist in protein refolding. The interaction between nChaps and proteins plays an important role in nChaps performing chaperone-like functions, but the interaction mechanism remains elusive. In this work, a series of nChaps with tunable hydrophilic-hydrophobic surfaces are prepared, and the process of nChaps-assisted denatured protein refolding is systematically explored. It is found that an appropriate hydrophilic-hydrophobic balance on the nChap surface is critical for enhancing protein renaturation. This is because only the optimal interaction between nChap and protein can simultaneously guarantee the suitable capture and sufficient release of client proteins. The findings in this work will provide an effective reference for the design of nChaps and contribute to the development of the potential of nChaps in the future.

Possibility for double optimization of siRNA intracellular delivery efficiency and antibacterial activity: Structure screening of pH-sensitive triblock amphiphilic polycation micelles.

Optimal combination of hydrophobic-hydrophilic balance, proton buffering and electrostatic interaction is the key issue for designing polycations as efficient gene vectors and antibacterial agents. Herein, we screened a series of pH-sensitive quaternary ammonium-based amphiphilic triblock copolymers, mPEG2k-P(DPAa/DMAb)-PQAc (TDDE-x), which had different pKa values and proton buffering capacities. Significantly, we found that both the highest siRNA intracellular delivery efficiency and the strongest antibacterial capacity occurred on TDDE-3 micelles with the segment structure of mPEG2k-P(DPA50/DMA56)-PQA55. The TDDE-3/siRNA complex achieved 67% silencing efficiency on H9C2 cells (N/P = 5, 50 nM siRNA), higher than the advanced commercial transfection reagents RNAiMAX (58%) and Lipo2000 (30%). Moreover, TDDE-3 micelles showed quite low MICs of 32 µg/mL and 8 µg/mL against E. coli and S. aureus, respectively. Further studies on the structure-function relationship indicated that TDDE-3 micelles could mediate robust endosome escape and siRNA cytosolic release, and strong bacterial cell membrane-destabilizing function. Undoubtedly, this work reveals the possibility for double optimization of siRNA intracellular delivery efficiency and antibacterial activity of amphiphilic polycations by reasonable structure design, which is significant for low-cost development and clinical translation of efficient multifunctional polycations.

Combating drug-resistant bacterial infection using biodegradable nanoparticles assembled from comb-like polycarbonates grafted with amphiphilic polyquaternium.

Bacterial infection is a serious clinical threat. The misuse of antibiotics has already resulted in the emergence of antibiotic-resistant strains of pathogenic bacteria. Efficient membrane-destructive antibacterial agents are considered as an alternative, promising solution against bacterial infection. Herein, we prepared a new type of comb-like cationic, polyethylene glycol (PEG) block polycarbonates with polyquaternium arms (G-CgQAs). The amphiphilic G-CgQAs could self-assemble into about 60 nm sized nanoparticles (NPs) with positive charges (20~30 mV). G-CgQA-3 NPs with an appropriate hydrophobic-hydrophilic balance in the polyquaternium arms showed antibacterial activity against Gram-negative, Gram-positive, and drug-resistant strains at low concentrations (MIC 64-128 µg mL-1) and low hemolysis (HC50 > 2000 µg mL-1). In vivo anti-infection tests indicated G-CgQA-3 NPs could highly inhibit the growth of vancomycin-resistant bacteria by spraying on wounds. Collectively, G-CgQA NPs hold great promise for the prevention of infection, serving as new antibacterial agents. This study also highlights the significance of a hydrophobic block in positive polyquaternium arms to facilitate the antibacterial activity of cationic, quaternized polymers. The design of comb-like amphiphilic cationic polycarbonates provides a new method for manufacturing antibacterial nano-agents.

Screening and Matching Amphiphilic Cationic Polymers for Efficient Antibiosis.

The amphiphilic cationic polymers that mimic antimicrobial peptides have received increasing attention due to their excellent antibacterial activity. However, the relationship between the structure of cationic polymers and its antibacterial effect remains unclear. In our current work, a series of PEG blocked amphiphilic cationic polymers composed of hydrophobic alkyl-modified and quaternary ammonium salt (QAS) moieties have been prepared. The structure-antibacterial activity relationship of these cationic polymers was investigated against E. coli and S. aureus, including PEGylation, random structure, molecular weights, and the content and lengths of the hydrophobic alkyl side chains. The results indicated that PEGylated random amphiphilic cationic copolymer (mPB35/T57) showed stronger antibacterial activity and better biocompatibility than the random copolymer without PEG (PB33/T56). Furthermore, mPB35/T57 with appropriate mole fraction of alkyl side chains (falkyl = 0.38), degree of polymerization (DP = 92), and four-carbon hydrophobic alkyl moieties was found to have the optimal structure that revealed the best antibacterial activities against both E. coli (MIC = 8 µg/mL, selectivity > 250) and S. aureus (MIC = 4 µg/mL, selectivity > 500). More importantly, mPB35/T57 could effectively eradicate E. coli biofilms by killing the bacteria embedded in the biofilms. Therefore, the structure of mPB35/T57 provided valuable information for improving the antibacterial activity of cationic polymers.

Synthesis and biological evaluation of novel 1-(aryl-aldehyde-oxime)uracil derivatives as a new class of thymidine phosphorylase inhibitors.

A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC50 values ranging between 0.12 ± 0.05 and 7.2 ± 1.4 µM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC50 is from 10.7 to 39.9 µM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis.

Tautomeric-Dependent Lactam Cycloaddition with Nitrile Oxide: Facile Synthesis of 1,2,4-Oxadiazole[4,5-a]indolone Derivatives.

A concise, metal-free, and gram-scale strategy to convert indoline-2,3-diones to 1,2,4-oxadiazole[4,5-a]indolones through an improved [3 + 2] cycloaddition of α-ketone-lactam with nitrile oxides has been developed. The lactim form of the resonance structure of isatin in protic solvents is the key active dipolarophile that shows chemo- and regioselectivity under experimental and theoretical conditions. This strategy conveniently enabled the assembly of several 1,2,4-oxadiazole[4,5-a]indolines with a broad range of functional groups. Compounds 3a and 4b exhibit cytotoxicity in the NCI/ADR-RES, SKOV3, and OVCAR8 cell lines.