Discovery of novel ß-carboline-1,2,3-triazole hybrids as AChE/GSK-3ß dual inhibitors for Alzheimer's disease treatment.

Alzheimer's disease (AD) is characterized by progressive cognitive impairment and mental behavior. The combination inhibition of two essential AD targets, acetylcholinesterase (AChE) and glycogen synthase kinase-3ß (GSK-3ß), might be a breakthrough in the discovery of therapeutic success. Herein, 17 ß-carboline-1,2,3-triazole hybrids were designed, synthesized, and evaluated for their AChE and GSK-3ß inhibitory potential. The results indicated that compound 21 has the most potent inhibition against eeAChE (IC50 = 0.20 ± 0.02 µM), hAChE (IC50 = 0.34 ± 0.01 µM) and GSK-3ß (IC50 = 1.14 ± 0.05 µM) among these compounds. In addition, it inhibited hAChE in a mixed type manner and could occupy the binding pocket forming diverse interactions with the target of AChE and GSK-3ß. Moreover, compound 21 showed low cytotoxicity against SH-SY5Y and HepG2 cell lines and good BBB permeability. Compound 21 also attenuated the tau hyperphosphorylation in the Tau (P301L) 293T cell model. The ADME projection exhibited that compound 21 has acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and GSK-3ß dual inhibition as a promising strategy for AD treatment.

Transformable Dual-Inhibition System Effectively Suppresses Renal Cancer Metastasis through Blocking Endothelial Cells and Cancer Stem Cells.

Tumor vasculature and cancer stem cells (CSCs) accelerate the development of metastatic renal cancer. Dual inhibition of vascular endothelium and CSCs is still a challenge due to their different pathological features. Herein, a transformable dual-inhibition system (TDS) based on a self-assembly peptide is proposed to construct nanofibrous barriers on the cell membrane in situ, which contributes to 1) reducing endothelial permeability and angiogenesis; and 2) inhibiting stemness and metastasis of CSCs in renal cancer. TDS specifically targets overexpressed receptor CD105 that provides the possibility to modulate both endothelial cells and CSCs for cancer therapy. Subsequently, owing to ligand-receptor interaction-induced transformation, the nanofibers form a barrier on the cell membrane. For vascular endothelium, TDS reduces the vascular permeability to 67.0% ± 4.7% and decreases angiogenesis to 62.0% ± 4.0%, thereby preventing the renal cancer metastasis. For human-derived CSCs, TDS inhibits stemness by reducing endogenic miR-19b and its transportation via CSCs-derived exosomes, which increases PTEN expression and consequently suppresses CSCs-mediated metastasis. In patient-derived xenograft mice, TDS significantly inhibits the tumorigenesis and angiogenesis. It also reduces the metastatic nodules in lung 5.0-fold compared with the control group. TDS opens up a promising avenue for suppressing the metastasis of cancer.

Viriditoxin Stabilizes Microtubule Polymers in SK-OV-3 Cells and Exhibits Antimitotic and Antimetastatic Potential.

Microtubules play a crucial role in mitosis and are attractive targets for cancer therapy. Recently, we isolated viriditoxin, a cytotoxic and antibacterial compound, from a marine fungus Paecilomyces variotii. Viriditoxin has been reported to inhibit the polymerization of bacterial FtsZ, a tubulin-like GTPase that plays an essential role in bacterial cell division. Given the close structural homology between FtsZ and tubulin, we investigated the potential antimitotic effects of viriditoxin on human cancer cells. Viriditoxin, like paclitaxel, enhanced tubulin polymerization and stabilized microtubule polymers, thereby perturbing mitosis in the SK-OV-3 cell line. However, the morphology of the stabilized microtubules was different from that induced by paclitaxel, indicating subtle differences in the mode of action of these compounds. Microtubule dynamics are also essential in cell movement, and viriditoxin repressed migration and colony formation ability of SK-OV-3 cells. Based on these results, we propose that viriditoxin interrupts microtubule dynamics, thus leading to antimitotic and antimetastatic activities.

Targeting cyclin-dependent kinases: From pocket specificity to drug selectivity.

The development of selective modulators of cyclin-dependent kinases (CDKs), a kinase family with numerous members and functional variations, is a significant preclinical challenge. Recent advancements in crystallography have revealed subtle differences in the highly conserved CDK pockets. Exploiting these differences has proven to be an effective strategy for achieving excellent drug selectivity. While previous reports briefly discussed the structural features that lead to selectivity in individual CDK members, attaining inhibitor selectivity requires consideration of not only the specific structures of the target CDK but also the features of off-target members. In this review, we summarize the structure-activity relationships (SARs) that influence selectivity in CDK drug development and analyze the pocket features that lead to selectivity using molecular-protein binding models. In addition, in recent years, novel CDK modulators have been developed, providing more avenues for achieving selectivity. These cases were also included. We hope that these efforts will assist in the development of novel CDK drugs.

Photostable Cascade-Activatable Peptide Self-Assembly on a Cancer Cell Membrane for High-Performance Identification of Human Bladder Cancer.

Missed or residual tumor burden results in high risk for bladder cancer relapse. However, existing fluorescent probes cannot meet the clinical needs because of inevitable photobleaching properties. Performance can be improved by maintaining intensive and sustained fluorescence signals via resistance to intraoperative saline flushing and intrinsic fluorescent decay, providing surgeons with sufficiently clear and high-contrast surgical fields, avoiding residual tumors or missed diagnosis. This study designs and synthesizes a photostable cascade-activatable peptide, a target reaction-induced aggregation peptide (TRAP) system, which can construct polypeptide-based nanofibers in situ on the cell membrane to achieve long-term and stable imaging of bladder cancer. The probe has two parts: a target peptide (TP) targets CD44v6 to recognize bladder cancer cells, and a reaction-induced aggregation peptide (RAP) is introduced, which effectively reacts with the TP via a click reaction to enhance the hydrophobicity of the whole molecule, assembling into nanofibers and further nanonetworks. Accordingly, probe retention on the cell membrane is prolonged, and photostability is significantly improved. Finally, the TRAP system is successfully employed in the high-performance identification of human bladder cancer in ex vivo bladder tumor tissues. This cascade-activatable peptide molecular probe based on the TRAP system enables efficient and stable imaging of bladder cancer.

Tailoring high-energy storage NaNbO3-based materials from antiferroelectric to relaxor states.

Reversible field-induced phase transitions define antiferroelectric perovskite oxides and lay the foundation for high-energy storage density materials, required for future green technologies. However, promising new antiferroelectrics are hampered by transition´s irreversibility and low electrical resistivity. Here, we demonstrate an approach to overcome these problems by adjusting the local structure and defect chemistry, delivering NaNbO3-based antiferroelectrics with well-defined double polarization loops. The attending reversible phase transition and structural changes at different length scales are probed by in situ high-energy X-ray diffraction, total scattering, transmission electron microcopy, and nuclear magnetic resonance spectroscopy. We show that the energy-storage density of the antiferroelectric compositions can be increased by an order of magnitude, while increasing the chemical disorder transforms the material to a relaxor state with a high energy efficiency of 90%. The results provide guidelines for efficient design of (anti-)ferroelectrics and open the way for the development of new material systems for a sustainable future.

Fundamental workings of chemical substitution at the A-site of perovskite oxides- a 207Pb NMR study of Ba-substituted PbZrO3.

Lead zirconate (PbZrO3, PZ) is a prototype antiferroelectric (AFE) oxide from which state-of-the-art energy storage materials are derived by chemical substitutions. A thorough understanding of the structure-property relationships of PZ-based materials is essential for both performance improvement and the design of more environmentally friendly replacements. (Pb1-xBax)ZrO3 (PBZ) can serve as a model system for studying the effect of A-site substitution in the perovskite lattice, with barium destabilizing the AFE state. Here, the two-dimensional 207Pb solid-state NMR spectra of PZ and PBZ were recorded to analyze the local structural role of barium substitution. At low substitution levels, 207Pb NMR spectroscopy reveals the presence of Pb-O bond length disorder. Upon crossing the threshold value of x for the macroscopic phase transition into a ferroelectric (FE) state, the barium cations cause local-scale lattice expansions in their vicinity, resulting in the collapse of two lead lattice sites into one. The stabilization of the larger volume site coincides with the favoring of larger lead displacements. We also observed more covalent bonding environments which may originate from the lower polarizability of the barium cations, facilitating the formation of stronger Pb-O bonds in their vicinity. From the local structural point of view, we propose that the substitution-induced AFE → FE phase transition is therefore related to an increasing correlation of larger lead displacements in larger oxygen cavities as the barium content increases. Our results also highlight 207Pb NMR spectroscopy as a valuable method for the characterization of the structure-property relationships of PbZrO3-based AFE and FE oxides.

Coherent Precipitates with Strong Domain Wall Pinning in Alkaline Niobate Ferroelectrics.

High-power piezoelectric applications are predicted to share approximately one-third of the lead-free piezoelectric ceramic market in 2024 with alkaline niobates as the primary competitor. To suppress self-heating in high-power devices due to mechanical loss when driven by large electric fields, piezoelectric hardening to restrict domain wall motion is required. In the present work, highly effective piezoelectric hardening via coherent plate-like precipitates in a model system of the (Li,Na)NbO3 (LNN) solid solution delivers a reduction in losses, quantified as an electromechanical quality factor, by a factor of ten. Various thermal aging schemes are demonstrated to control the average size, number density, and location of the precipitates. The established properties are correlated with a detailed determination of short- and long-range atomic structure by X-ray diffraction and pair distribution function analysis, respectively, as well as microstructure determined by transmission electron microscopy. The impact of microstructure with precipitates on both small- and large-field properties is also established. These results pave the way to implement precipitate hardening in piezoelectric materials, analogous to precipitate hardening in metals, broadening their use cases in applications.

Deciphering the phase transition-induced ultrahigh piezoresponse in (K,Na)NbO3-based piezoceramics.

Here, we introduce phase change mechanisms in lead-free piezoceramics as a strategy to utilize attendant volume change for harvesting large electrostrain. In the newly developed (K,Na)NbO3 solid-solution at the polymorphic phase boundary we combine atomic mapping of the local polar vector with in situ synchrotron X-ray diffraction and density functional theory to uncover the phase change and interpret its underlying nature. We demonstrate that an electric field-induced phase transition between orthorhombic and tetragonal phases triggers a dramatic volume change and contributes to a huge effective piezoelectric coefficient of 1250 pm V-1 along specific crystallographic directions. The existence of the phase transition is validated by a significant volume change evidenced by the simultaneous recording of macroscopic longitudinal and transverse strain. The principle of using phase transition to promote electrostrain provides broader design flexibility in the development of high-performance piezoelectric materials and opens the door for the discovery of high-performance future functional oxides.

An Ultrasound-Induced Self-Clearance Hydrogel for Male Reversible Contraception.

Nearly half of pregnancies worldwide are unintended mainly due to failure of contraception, resulting in negative effects on women's health. Male contraception techniques, primarily condoms and vasectomy, play a crucial role in birth control, but cannot be both highly effective and reversible at the same time. Herein, an ultrasound (US)-induced self-clearance hydrogel capable of real-time monitoring is utilized for in situ injection into the vas deferens, enabling effective contraception and noninvasive recanalization whenever needed. The hydrogel is composed of (i) sodium alginate (SA) conjugated with reactive oxygen species (ROS)-cleavable thioketal (SA-tK), (ii) titanium dioxide (TiO2), which can generate a specific level of ROS after US treatment, and (iii) calcium chloride (CaCl2), which triggers the formation of the hydrogel. For contraception, the above mixture agents are one-time injected into the vas deferens, which can transform from liquid to hydrogel within 160 s, thereby significantly physically blocking the vas deferens and inhibiting movability of sperm. When fertility is needed, a noninvasive remedial ultrasound can make TiO2 generate ROS, which cleaves SA-tK to destroy the network of the hydrogel. Owing to the recanalization, the refertility rate is restored to 100%. Meanwhile, diagnostic ultrasound (D-US, 22 MHz) can monitor the occlusion and recanalization process in real-time. In summary, the proposed hydrogel contraception can be a reliable, safe, and reversible male contraceptive strategy that addresses an unmet need for men to control their fertility.

Fe(III) Ions-Assisted Aniline Polymerization Strategy to Nitrogen-Doped Carbon-Supported Bimetallic CoFeP Nanospheres as Efficient Bifunctional Electrocatalysts toward Overall Water Splitting.

It remains an urgent demand and challenging task to design and fabricate efficient, stable, and inexpensive catalysts toward sustainable electrochemical water splitting for hydrogen production. Herein, we explored the use of Fe(III) ion-assisted aniline polymerization strategy to embed bimetallic CoFeP nanospheres into the nitrogen-doped porous carbon framework (referred CoFeP-NC). The as-prepared CoFeP-NC possesses excellent hydrogen evolution reaction (HER) performance with the small overpotential (η10) of 81 mV and 173 mV generated at a current density of 10 mA cm-2 in acidic and alkaline media, respectively. Additionally, it can also efficiently catalyze water oxidation (OER), which shows an ideal overpotential (η10) of 283 mV in alkaline electrolyte (pH = 14). The remarkable catalytic property of CoFeP-NC mainly stems from the strong synergetic effects of CoFeP nanospheres and carbon network. On the one hand, the interaction between the two can make better contact between the electrolyte and the catalyst, thereby providing a large number of available active sites. On the other hand, it can also form a network to offer better durability and electrical conductivity (8.64 × 10-1 S cm-1). This work demonstrates an efficient method to fabricate non-noble electrocatalyst towards overall water splitting, with great application prospect.

Precipitation Hardening in Ferroelectric Ceramics.

Domain wall motion in ferroics, similar to dislocation motion in metals, can be tuned by well-concepted microstructural elements. In demanding high-power applications of piezoelectric materials, the domain wall motion is considered as a lossy hysteretic mechanism that should be restricted. Current applications for so-called hard piezoelectrics are abundant and hinge on the use of an acceptor-doping scheme. However, this mechanism features severe limitations due to enhanced mobility of oxygen vacancies at moderate temperatures. By analogy with metal technology, the authors present here a new solution for electroceramics, where precipitates are utilized to pin domain walls and improve piezoelectric properties. Through a sequence of sintering, nucleation, and precipitate growth, intragranular precipitates leading to a fine domain structure are developed as shown by transmission electron microscopy, piezoresponse force microscopy, and phase-field simulation. This structure impedes the domain wall motion as elucidated by electromechanical characterization. As a result, the mechanical quality factor is increased by ≈50% and the hysteresis in electrostrain is suppressed considerably. This is even achieved with slightly increased piezoelectric coefficient and electromechanical coupling factor. This novel process can be smoothly implemented in industrial production processes and is accessible to simple laboratory experimentation for microstructure optimization and implementation in various ferroelectric systems.

A Near-Infrared Peptide Probe with Tumor-Specific Excretion-Retarded Effect for Image-Guided Surgery of Renal Cell Carcinoma.

Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvß3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.

Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ12, 14-prostaglandin J2.

In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ12, 14-prostaglandin J2 (15 d-PGJ2). The exocyclic enone moiety of 15 d-PGJ2 is essential for covalent bonding with the Cys285 residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ2. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)-6a1 was suggested as a potential PPAR-γ ligand.

A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5-Fluorouracil by reversing Notch and epithelial-mesenchymal transition in vitro and in vivo.

OBJECTIVES: Colorectal cancer is one of the most common malignancies both in men and women. Owing to metastasis and resistance, the prognosis of colorectal cancerCRC patients remains extremely poor with chemotherapy. A disintegrin and metalloproteinase 17 (ADAM17) induces the activation of Notch pathway and contributes to the chemoresistance. This study aimed to discover a novel ADAM17 inhibitor and investigate the chemosensitization effect. MATERIALS AND METHODS: Pharmacophore model, western blot and enzymatic assay were used to discover ZLDI-8. Cell proliferation was determined by MTT and colony formation assay. Cell migratory and invasive ability were determined by wound healing scratch and transwell assay. Immunofluorescence images and western blot analysed the expression of Notch or epithelial-mesenchymal transition (EMT) pathway markers. Xenografts were employed to evaluate the chemosensitization effect of ZLDI-8 in vivo. RESULTS: We found that ZLDI-8 cell-specifically inhibited the proliferation of CRC, and this effect was due to abrogation of ADAM17 and Notch pathway. Meanwhile, we reported for the first time that ZLDI-8 synergistically improved the anti-tumour and anti-metastasis activity of 5-fluorouracil or irinotecan by reversing Notch and EMT pathways. Interestingly, in vivo studies further demonstrated that ZLDI-8 promoted the anti-tumour effect of 5-fluorouracil through Notch and EMT reversal. CONCLUSIONS: A novel ADAM17 inhibitor ZLDI-8 may be a potential chemosensitizer which sensitized CRC cells to 5-fluorouracil or irinotecan by reversing Notch and EMT pathways.