Nuclear Targeting of Methyl-Recycling Enzymes in Arabidopsis thaliana Is Mediated by Specific Protein Interactions

Numerous transmethylation reactions are required for normal plant growth and development. S-adenosylhomocysteine hydrolase （SAHH） and adenosine kinase （ADK） act coordinately to recycle the by-product of these reactions, S-adenosylhomocysteine （SAH） that would otherwise competitively inhibit methyltransferase （MT） activities. Here, we report on investigations to understand how the SAH produced in the nucleus is metabolized by SAHH and ADK. Localization analyses using green fluorescent fusion proteins demonstrated that both enzymes are capable of localizing to the cytoplasm and the nucleus, although no obvious nuclear localization signal was found in their sequences. Deletion analysis revealed that a 41-amino-acid segment of SAHH （GlylS^-Lys19~） is required for nuclear targeting of this enzyme. This segment is surface exposed, shows unique sequence conservation patterns in plant SAHHs, and possesses additional features of protein-protein interaction motifs. ADK and SAHH interact in Arabidopsb via this segment and also interact with an mRNA cap MT. We propose that the targeting of this complex is directed by the nuclear localization signal of the MT; other MTs may similarly target SAHH/ADK to other subcellular compartments to ensure uninterrupted transmethylation.

One-pot synthesis of nuclear targeting carbon dots with high photoluminescence

Carbon dots(CDs) are novel fluorescent nanomaterials with good water solubility, high resistance to photobleaching and low toxicity. While, there are few studies elaborate on the relationship among reaction conditions, properties and applications of CDs. In this study, a series of CDs are synthesized through a one-pot hydrothermal method, and different reaction conditions are carried out to study the influencing factors of CDs properties. As a result, with the increase of temperature and reaction time, the particle size and zeta potential of CDs increased, the maximum emission wavelength red-shifted and the fluorescence quantum yield(QY) improved. Among them, CD3006 has good water solubility and highest QY of 81.4%, which is beneficial for its applications in bioimaging and ion detection. CD3006 is almost nontoxic in cells at a concentration of 500 μg/m L. In addition, the positive charged CD3006 shows nuclear targeting potential because of its combination with DNA through electrostatic interaction in nucleus. The properties of CDs can be greatly enhanced by controlling reaction conditions, and it provides great application prospects.

Chemical Design of Nuclear-Targeting Mesoporous Silica Nanoparticles for Intra-nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA-toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer ceils. Here, we demonstrate the first paradigm estabJished in our laboratory in developing nucle- ar-targeted drug delivery systems （DDSs） based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the ctinics. Firstly, nuclear-targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs-based and nuclear-targeted drug/agent delivery strategy was further applied to overcome multidrug resistance （MDR） of malignant tumors, intra-nuclearly deliver therapeutic genes, photosensitizers, radio-enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.

A tumor-penetrable drug nanococktail made from human histones for interventional nucleus-targeted chemophotothermal therapy of drug-resistant tumors

Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser.After localized intervention,DIR825@histone penetrated tumor tissues by transcytosis,efficiently entered tumor cells and targeted the cell nuclei.DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release.Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting.Moreover,an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury.Therefore,DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.