Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 µM) with pyrimidone compound 5 (GSK-3ß: IC50 = 3 µM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: IC50 = 0.930 ± 0.080 µM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 µM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.

Discovery of a Dual Tubulin and Neuropilin-1 (NRP1) Inhibitor with Potent In Vivo Anti-Tumor Activity via Pharmacophore-based Docking Screening, Structure Optimization, and Biological Evaluation.

Dual inhibition of tubulin and neuropilin-1 (NRP1) may become an effective method for cancer treatment by simultaneously killing tumor cells and inhibiting tumor angiogenesis. Herein, we identified dual tubulin/NRP1-targeting inhibitor TN-2, which exhibited good inhibitory activity against both tubulin polymerization (IC50 = 0.71 ± 0.03 µM) and NRP1 (IC50 = 0.85 ± 0.04 µM). Importantly, it significantly inhibited the viability of several human prostate tumor cell lines. Further mechanism studies indicated that TN-2 could inhibit tubulin polymerization and cause G2/M arrest, thereby inducing cell apoptosis. It could also suppress cell tube formation, migration, and invasion. Moreover, TN-2 showed obvious antitumor effects on the PC-3 cell-derived xenograft model with negligible side effects and good pharmacokinetic profiles. These data demonstrate that TN-2 could be a promising dual-target chemotherapeutic agent for the treatment of prostate cancer.

Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation.

Excessive melanin deposition may lead to a series of skin disorders. The production of melanin is carried out by melanocytes, in which the enzyme tyrosinase performs a key role. In this work, we identified a series of novel tyrosinase inhibitor hybrids with a dihydrochalcone skeleton and resorcinol structure, which can inhibit tyrosinase activity and reduce the melanin content in the skin. Compound 11c possessed the most potent activity against tyrosinase, showing IC50 values at nanomolar concentration ranges, along with significant antioxidant activity and low cytotoxicity. Furthermore, in vitro permeation tests, supported by HPLC analysis and 3D OrbiSIMS imaging visualization, revealed the excellent permeation of 11c. More importantly, compound 11c reduced the melanin content on UV-induced skin pigmentation in a guinea pig model in vivo. These results suggest that compound 11c may serve as a promising potent tyrosinase inhibitor for the development of a potential therapy to treat skin hyperpigmentation.

Spirolactone-type and enmein-type derivatives as potential anti-cancer agents derived from oridonin.

Natural products (NPs) are always the important sources in the field of drug discovery, among which spirolactone-type and enmein-type compounds exhibit a wide range of biological activities, especially anti-tumor activity. Based on previous studies, the spirolactone-type and enmein-type compounds could be derived from natural oridonin (1) by several chemical reactions. Herein, a series of novel spirolactone-type and enmein-type derivatives with different aryl allyl ester substitutions at their C-14 hydroxyl group were designed and synthesized. The anti-tumor activity results showed that most of the compounds exhibited better anti-proliferative activities than parent compound oridonin, and the most potent compound had an IC50 value of 0.40 µM in K562 cells. Further mechanistic studies revealed that the optimal compound could arrest K562 cells at G2/M phase by inhibiting cdc-2, cdc-25c and cyclin B1 expression. In addition, the optimal compound induced apoptosis in K562 cells through increasing ROS production and depolarizing mitochondrial membrane potential. Collectively, these valuable results suggested that the most potent compound could be an anti-tumor agent candidate and is worthy of further investigation.

Effect of poly-γ-glutamic acid on hydration and structure of wheat gluten.

In recent years, hydrocolloids have been used extensively as enhancers in dough products. However, studies on the effect of hydrophilic polymers on wheat gluten (WG) within the dough are scarce. In the present study, poly-γ-glutamic acid (γ-PGA), a new and healthy food additive, was added to the WG to investigate its effect on hydration, rheological properties, and structures of WG. Results showed that with the addition of γ-PGA, the water-holding capacity (WHC) of WG and the content of bound water increased, whereas the content of immobilized water decreased. In addition, γ-PGA changed the rheological properties of WG. The elastic properties of WG gradually weakened and the viscous properties gradually increased. Furthermore, scanning electron microscopy (SEM) results showed that with the addition of γ-PGA, the structure of the WG network became more uniform and the pore size was smaller. A change also occurred in the secondary structure of WG, in which the α-helix content was significantly reduced while the contents of ß-turn angles were significantly increased, thereby suggesting that γ-PGA not only functions as a filler in the WG system, but also interacts with WG. From the present study, we conclude that γ-PGA can interact with WG and water to change the WG secondary structure. γ-PGA can also restrict moisture migration and enhance the WHC of WG, thereby changing the WG microstructure and improving its functional properties. This condition provides the basis for γ-PGA to be recommended as WG enhancer for addition in WG-containing products such as bread, seitan (meat replacement), and others. PRACTICAL APPLICATION: WG performance plays a key role in the quality of flour products. Thus, many studies have been conducted to improve the WG quality to produce highly popular flour products. The results of this study showed that γ-PGA can interact with WG and water, and had a good effect on improving the WHC of WG, which means that γ-PGA has potential usefulness in improving the quality of WG and WG-containing products such as bread, seitan (meat replacement), and others.

Adsorption of Cd(II) in water by mesoporous ceramic functional nanomaterials.

Mesoporous ceramic functional nanomaterials (MCFN) is a self-assembled environmental adsorbent with a monolayer molecular which is widely used in the treatment of industrial wastewater and contaminated soil. This work aimed to study the relationship between the adsorption behaviour of Cd(II) by MCFN and contact time, initial concentration, MCFN dosage, pH, oscillation rate and temperature through a batch adsorption method. The adsorption kinetic and isotherm behaviours were well described by the pseudo-second-order and Langmuir models. The batch characterization technique revealed that MCFN had several oxygen-containing functional groups. Using Langmuir model, the maximum adsorption capacity of MCFN for Cd(II) was 97.09 mg g-1 at pH 6, 25°C, dosage of 0.2 g and contact time of 180 min. Thermodynamic study indicated that the present adsorption process was feasible, spontaneous and exothermic at the temperature range of 25-55°C. The results of this study provide an important enlightenment for Cd removal or preconcentration of porous ceramic nanomaterial adsorbents for environmental applications.

Toward a simple way for a mechanochromic luminescent material with high contrast ratio and fatigue resistance: Implication for information storage.

In this work, we present the synthesis and photoluminescence (PL) behaviour of a new compound, DHNC. The molecular design includes twisted conformation and the incorporation of electron donor (D) and acceptor (A) pairs, which endows the compound with both twisted intramolecular charge transfer (ICT) and aggregation-induced emission (AIE) properties. Importantly, the compound exhibits mechanochromic luminescence (MCL): The emission of the crystalline powder shows strong green emission but turns into orange-red with an obvious quenching effect after grinding, demonstrating a high contrast ratio. The emission of the ground sample can be rejuvenated though recrystallization by either immersion or fumigation in common organic solvents. The emission can be reversibly switched between two states for more than 10 cycles, showing fatigue resistance. In a quantitative mechanical experiment, the DHNC-loaded film has a remarkable emission loss with the external force up to 67.9 Mpa, showing high sensitivity. An archetype of information storage is developed based on this MCL material, which uses mechanical force to write information and organic vapour to erase. Letters and cartoon pictures can be written and erased repeatedly on the DHNC-loaded film, indicating high contrast ratio and fatigue resistance.

The effects of jolkinolide B on HepG2 cells as revealed by 1H-NMR-based metabolic profiling.

Jolkinolide B (JB), which is isolated from the dried root of Euphorbia fischeriana Steud., has been reported to possess various therapeutic effects, such as treatment of edema and abdominal distention and protection against acute lung injury, and it has also been reported to have anti-inflammatory even antitumor properties. Thus, JB has always been considered a promising anticancer drug candidate. In the current work, a cellular metabolomics evaluation based on the nuclear magnetic resonance (NMR) approach was applied to investigate the mechanism of JB in HepG2 cells. In addition, biological assays such as the MTT assay, DAPI staining and the Annexin V-FITC/PI assay were implemented to evaluate cell viability and apoptosis in JB-treated cells. Subsequently, we used multivariate statistical analyses, such as principal component analysis (PCA) and orthogonal projection to latent structure with discriminant analysis (OPLS-DA) to identify metabolic biomarkers. In total, 36 metabolites in the cell extract samples and 30 metabolites in the cell culture media samples were clearly identified to be altered after the treatment. Variations in the specific metabolites suggested that HepG2 cells that were exposed to JB displayed the disordered effects in multiple metabolic pathways, such as the tricarboxylic acid cycle, amino acid metabolism, GSH synthesis and pyruvate metabolism. NMR-based cell metabolomics provided a holistic method for the identification of JB's antitumor mechanisms and the exploration of its potential applications in preclinical and clinical studies.

Tissue metabolomics study to reveal the toxicity of a traditional Tibetan medicine 'Renqing Changjue' in rats.

Renqing Changjue (RQCJ), a precious Traditional Tibetan Medicine (TTM), has been widely used in the management of diseases of the digestive system, toxinosis and pyreticosis. However, in the formula, a significant level of heavy metals, which are potential toxic elements, are present. Therefore, it is important to assess the toxicity of RQCJ dynamically and holistically. In the present study, a 1H NMR metabolomics approach and inductively coupled plasma mass spectrometry (ICP-MS) were implemented to analyze the samples of liver, kidney and spleen from rats treated with RQCJ. The results revealed that 9 metabolites in the liver, 13 metabolites in the kidney and 16 metabolites in the spleen were significantly altered, which suggest that disturbances in TCA cycle, amino acid metabolism, energy metabolism and oxidative stress are produced by successive administration of RQCJ over 15 days. Complemented by histopathology and biochemical assay, the trends of the metabolite levels indicate that RQCJ caused tissue injury to a certain extent, which was evidenced by the high levels of As and Hg in the tissue. The toxic effects of RQCJ were alleviated in liver and kidney during the recovery period, and RQCJ may cause long-term damage in spleen. These findings provide a significant experimental proof on the estimated safety and valuable information about the metabolism of RQCJ, which will be valuable in determining the health risks of the drug.