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Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ(1-42) mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Aβ(1-42) mice. Furthermore, lonafarnib enhanced α7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Aβ(1-42) mice, which were inhibited by α7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Aβ(1-42) mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of α7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Aβ(1-42) mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Aβ(1-42) mice, which may be related to the improvement of BDNF content through the H-Ras-α7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition. SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. However, no effective drugs have not been developed for the treatment of AD synaptic. This study for the first time reported the beneficial effects of Ras inhibitor lonafarnib on the synaptic structure and function in AD mice, providing an alternative way for the treatment of “synaptic disease” in AD patients.

Human Papillomavirus (HPV) is the leading cause of cervical cancer, with only some HPV types prevented with vaccines and no treatments for the viral infection itself. One way to target viral infect...

Luminescent security printing is of particular importance in the information era. However, the use of conventional paper still carries a lot of economic and environmental issues. Therefore, developing new environmentally friendly security printing material with a low cost is imperative. To achieve the aforementioned goals, novel lanthanide polyoxometalate doped gelatin/glycerol films with high transparency, high strength, and good flexibility have been developed via a solution-casting method. The electrostatic interaction between zwitterionic gelatin and polyoxometalate was confirmed by attenuated total reflection Fourier transform infrared spectroscopy. Luminescent spectra and digital images indicated that the films exhibited reversible luminescent switching properties through association and dissociation of hydrogen bonds between glycerol and water molecules, allowing its potential application as water-jet rewritable paper for luminescent security printing. Furthermore, the printed information can be conveniently "erased" by heating, and the film can be reused for printing. The film exhibited excellent ability to be both rewritten and re-erased. A QR code pattern and hybrid printing were employed to improve the security of information. In addition, the rewritable films possessed excellent regeneration ability and low toxicity, as well as good stability against UV irradiation and organic solvents. The water-jet rewritable film based on lanthanide polyoxometalate for luminescent security printing, to the best of our knowledge, has not yet been reported up to date. This work provides an attractive alternative strategy on fabricating rewritable films for luminescent security printing in terms of cutting down the cost, simplifying the preparation process, and protecting the environment.

Anti-viral therapy has made remarkable strides in improving the quality of life of infected individuals over the past few decades. However, the emergence of adverse side effects and drug resistance highlights the need for alternate drugs with either different structures or distinct mechanisms of action. The virus capsid is an attractive therapeutic target owing to its high sequence conservation and essential role in the virus life cycle. The capsid protein can be affected by small molecules at different positions in several combinations, both in early and late steps in the cycles of virus infection and replication. Therefore, a variety of small molecules that bind to the capsid proteins have been developed, and some of them have shown promise for pre-clinical therapeutic development. In this review, we focus on the recent advances on small molecules targeting the capsid protein of several clinically related spherical viruses such as the hepatitis B virus (HBV), human immunodeficiency virus (HIV) and human papillomavirus (HPV), together with filoviruses such as Ebola in several distinct classes of (i) synthetic organics, (ii) natural products and their derivatives, and (iii) peptides. Hopefully, some of these preclinical capsid inhibitors will be approved for therapy within the next few years.

Two cationic dendrons bearing terminal groups of triethylene glycol monomethyl ether in different generations were used to encapsulate a paramagnetic polyoxometalate cluster K13[Gd(β2-SiW11O39)2], in which the Gd3+ ion was sandwiched by the coordination of two lacunary [β2-SiW11O39]8− sub-clusters, through electrostatic interaction. Benefiting from the surface covering of cationic dendrons and ionic complexation, both inorganic polyanionic core and the complexes formed maintained chemical stability in a physiological environment. In addition, the formed charge-neutralized supramolecular complex dendrimers with biocompatible periphery had low cytotoxicity but high relaxivity for in vitro and in vivo magnetic resonance imaging (MRI) in the self-assembled state. Because of the branched structure of organic components on the cluster surface and the disordered packing of complexes in aggregations, a reasonable communication of cluster core with the bulk environment was concluded. Importantly, due to the assembled particle size and molecular weight, the complex dendrimers were a suitable model for liver-specific MRI contrast agents. The results obtained showed that the dendritic supramolecular hybrid complexes represent potential MRI contrast agents in the development of new biomedical materials.

In an effort to improve both the stability of virus-like particles (VLPs) and the medical activity of polyoxometalates (POMs), a new hybrid assembly system between human papillomavirus (HPV) capsid protein L1 and a europium-containing POM (EuW10) has been constructed, for the first time, via the electrostatic interactions between them. The co-assembly of EuW10 and HPV 16 L1-pentamer (L1-p) in buffer solution resulted in the encapsulation of POMs in the cavity of VLPs, which was further confirmed by cesium chloride (CsCl) gradient ultracentrifugation, SDS-PAGE, dynamic light scattering, and transmission electron microscopy, whereas the post-assembly of EuW10 with the as-prepared VLPs leads to the adsorption of POMs only on the external surface of particles, and both cases improved the thermal and storage stabilities of VLPs obviously. Particularly, the encapsulation of POMs in VLPs largely improved the antibacterial activity of EuW10, and thereby, the present study will be significant for both the stabilit...

Two assembly modes have been constructed between double-strand DNA-protected silver nanoclusters (AgNCs-dsDNA) and human papillomavirus (HPV) 16 main capsid protein L1, respectively, which are well defined by CsCl gradient centrifugation, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The co-assembly leads to a large emission increase of AgNCs-dsDNA attributed to an assembly-induced luminescence enhancement (AILE), and vice versa in disassembly; however, the post-assembly does not. Therefore, a new approach to monitoring the assembly/disassembly of HPV virus-like particles (VLPs) is established accordingly. The study not only presents an AILE phenomenon for silver nanoclusters but also affords an easily performed fluorescence approach to evaluate HPV VLP assembly/disassembly directly, which could be extended to other kinds of metal nanoclusters protected by DNA as well as a kinetic study on the assembly of other species of virus.

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT), as non-invasive therapy approaches, have gained accumulated attention for cancer treatment in past years. PTT and PDT can generate local hyperthermia effects and reactive oxygen species (ROS) respectively, for tumor eradication. To improve the therapeutic performance while minimizing the reverse side effects of phototherapy, extensive efforts have been devoted to developing stimuli-activatable (e.g. pH, redox, ROS, enzyme, etc) nanomaterials for tumor-specific delivery/activation of the phototherapeutics. In this review, we first overviewed the recent advances of the engineered stimuli-responsive nanovectors for the phototherapy of cancer. We particularly summarized the progress of stimuli-activatable nanomaterials-based combinatory therapy strategies for augmenting the performance of phototherapy. We further discuss challenges for the clinical translation of nanomaterials-based phototherapy.

Although current human papillomavirus (HPV) vaccines can protect well against infection, they are effective only for a limited number of subtypes. Coupled with the dilemma that no efficient prescription is currently clinically available for therapy, there is an urgent need to develop new anti-HPV agents. In the present study l- and d-Proline modified calix[4]arenes (Pro-C4 A) were investigated to determine any differences in their effect on the assembly of HPV 16 L1 pentamer (L1-p). The mechanism of action using model peptides was investigated by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) and Nuclear Magnetic Resonance (NMR) and revealed that the binding was targeting the basic residues at L1 interface. This was also well supported by the trypsin digestion experiments and molecular simulations performed on the full-length L1. The large energy and morphology differences revealed by molecular simulations explain the binding disparity of l- and d-Pro-C4 A to L1, and consequently the selective inhibition of them on L1-p formation. The present study opens a way to develop enantioselective and cost-effective inhibitors for L1-p formation, which might be used as a new kind of anti-HPV agent and could be extended to other viruses based on similar mechanisms.

Glutathione S-transferase (GST) is distributed widely in tissues and has been proven to be vital in the body. For example, it catalyzes reduced glutathione (GSH) to a variety of electrophilic substances and thus protects cells against many toxic chemicals. Therefore, GST-related investigations have always been significant for medical and/or life sciences. In the present study, a new material of gold nanoclusters (Au-NCs) protected by GST, Au-NCs@GST, was fabricated via an improved one-step heating method. The products were fully characterized by X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), and Fourier transform infrared (FT-IR) and circular dichroism (CD) spectra. The results confirmed that around 10 gold atoms are encapsulated in one intact GST, forming Au-NCs@GST with strong (QY = 13.5%) red emission at 670 nm. Therefore, a new nanomaterial possessing both strong luminescence and bio-functions of GST was developed, and it has great potential in GST-related investigations. To prove the concept, Au-NCs@GST was successfully applied to detect metronidazole (MNZ) both in solution and in living cells. Therefore, in the present study, we report not only a new nanomaterial of Au-NCs@GST but also a feasible fluorescence probe for antibiotic detection. Both the improved synthetic method and the design concept can be extended to the fabrication of other kinds of metal nanoclusters using different functional proteins for various purposes.

Cervical cancer is the second-largest killer of women worldwide. Development of biomarkers that can be used to efficiently screen cervical cancer would be extremely useful for clinical management. The presence of human papillomavirus (HPV) capsid proteins, L1 and L2, is extremely important clinically and warrants further examination of cervical cancer. The present study supplied an easy, cost-effective and efficient fluorescence-enhanced method to detect the cationic peptides of HPV capsid proteins by using an Eu-containing polyoxometalate. The binding-induced luminescence enhancement of EuW10 was further successfully used to detect HPV L1 pentamers expressed from Escherichia coli, which could be extended to detect other proteins involving a large amount of polybasic segments. The present study showed an excellent application of a type of inorganic material, polyoxometalate, to viral and biological science.

The binding-induced luminescence enhancement of an Eu-containing polyoxometalate (POM), EuSiWMo, by the arginin/lysine-rich cationic peptides supplied a platform to detect the capsid proteins of human papillomaviruses (HPVs). However, the strong binding affinity between them makes it very difficult to be differentiated among peptides from different subtypes of HPVs. Therefore, several strategies to monitor the binding affinity of POM-peptide are performed and finally the discriminations on representative peptides from different subtypes of HPV capsid proteins are achieved in the present study. The results show that an Eu-containing POM, EuW10, with nine negative charges is sufficient to discriminate different subtypes of HPV peptides based on the specific sequence and basic charge differences. The discrimination mechanisms between them explored at sub-molecular level using time-resolved fluorescence spectra and isotherm titration calorimetric (ITC) reveal both the driving force and binding model accordingly. Therefore, this study reports a simple, low-cost and efficient fluorescence enhanced method to discriminate the peptides from different subtypes of HPV capsid proteins, which would be possible after further optimization.

Pillarenes and calixarenes showed obvious inhibition of HPV16 L1 pentamer formation via their selective binding to Arg and Lys residues at the monomer interface, which was reversible after the release of cyclic arenes. Pillarenes are more effective than calixarenes in terms of the inhibition efficiency, attributing to the different kinetics and binding affinity.

As a new type of cathepsin K inhibitor, azadipeptide nitriles have the characteristics of proteolytic stability and excellent inhibitory activity, but they exhibit barely any satisfactory selectivity. Great efforts have focused on improving their selectivity toward cathepsin K. In this sequential study, we report the further structural optimization, synthesis, molecular modeling, and in vitro enzymatic assays of a new series of potent and selective inhibitors of cathepsin K without the P2–P3 amide linker. Significant selective improvements were achieved for cathepsin K over L, S and B, and a triaryl meta-product 13′ possessed the favorable balance between potency (Ki = 0.29 nM) and selectivity of cathepsin K over cathepsin L (320-fold), S (1784-fold) and B (8566-fold). We undertook a covalent protein–ligand docking study to explain the improved selectivity of several representative compounds. Such a selectivity improvement would be useful to avoid harmful side effects in practical applications of these compounds.