Design, synthesis and biological evaluation of novel diosgenin-benzoic acid mustard hybrids with potential anti-proliferative activities in human hepatoma HepG2 cells.

To discover new lead compounds with anti-tumour activities, in the present study, natural diosgenin was hybridised with the reported benzoic acid mustard pharmacophore. The in vitro cytotoxicity of the resulting newly synthesised hybrids (8-10, 14a-14f, and 15a-15f) was then evaluated in three tumour cells (HepG2, MCF-7, and HeLa) as well as normal GES-1 cells. Among them, 14f possessed the most potential anti-proliferative activity against HepG2 cells, with an IC50 value of 2.26 µM, which was 14.4-fold higher than that of diosgenin (IC50 = 32.63 µM). Furthermore, it showed weak cytotoxicity against GES-1 cells (IC50 > 100 µM), thus exhibiting good antiproliferative selectivity between normal and tumour cells. Moreover, 14f could induce G0/G1 arrest and apoptosis of HepG2 cells. From a mechanistic perspective, 14f regulated cell cycle-related proteins (CDK2, CDK4, CDK6, cyclin D1 and cyclin E1) as well mitochondrial apoptosis pathway-related proteins (Bax, Bcl-2, caspase 9, and caspase 3). These findings suggested that hybrid 14f serves as a promising anti-hepatoma lead compound that deserves further research.

Dual Sensitization Anti-Resistant Nanoparticles for Treating Refractory Breast Cancers via Apoptosis-Inducing.

Purpose: Current chemotherapy fails to offer a desirable efficacy in clinical treatment against breast cancer due to the extensive multi-drug resistance. In this study, we developed dual sensitization anti-resistant nanoparticles to treat refractory breast cancer, aiming to benefit from photodynamic therapy and chemotherapy. Methods: Hyaluronic acid (HA) derivative and photosensitizer chlorin e6 (Ce6) derivative were synthesized and confirmed by mass spectrometry. These derivatives and the chemotherapy agent paclitaxel were incorporated into nanoparticles by an emulsion-solvent evaporation method. The prepared nanoparticles were characterized by dynamic laser scattering, atomic force microscopy, and high performance liquid chromatography (HPLC). The efficacy and mechanisms of the nanoparticles, both in vitro and in vivo, were investigated by flow cytometry, confocal/fluorescence microscopy, and a high-content screening system. Results: The prepared dual sensitization anti-resistant nanoparticles were round with a diameter of ~ 100 nm, exhibiting high encapsulation efficiency for the anticancer agent paclitaxel. The nanoparticles demonstrated a robust inhibitory effect against drug-resistant breast cancer cells by enhanced uptake, synergistic effect of photodynamic therapy and chemotherapy, and apoptosis-inducing via multiple pathways. In vivo efficacy, biocompatibility and safety were further confirmed acceptable in tumor-bearing mice. Conclusion: The prepared dual sensitization anti-resistant nanoparticles were promising to treat refractory breast cancer with a controllable treatment site and minimal side effects.

Novel diosgenin-amino acid-benzoic acid mustard trihybrids exert antitumor effects via cell cycle arrest and apoptosis.

In discovering new powerful antitumor agents, two series of novel diosgenin-amino acid-benzoic acid mustard trihybrids (7a-7 g and 12a-12 g) were designed and synthesized. The antiproliferative activities were tested against five human tumor cell lines and one normal cell line using CCK-8 assays. Among the trihybrids, 12e was the most promising compound, which inhibited T24 cells with IC50 value of 6.96 µM, and was stronger than its parent compound diosgenin (IC50 = 32.33 µM). In addition, 12e had weak cytotoxicity on the normal GES-1 cell line (IC50 = 213.74 µM). Moreover, 12e could cause G2/M cell cycle arrest, increase the percentage of apoptosis, induce mitochondrial depolarization, and promote reactive oxygen species generation in T24 cells. Further studies on antitumor mechanism demonstrated that 12e triggered the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways. More importantly, 12e could inhibit T24 cell proliferation in an in vivo zebrafish xenograft model. Therefore, 12e, as a novel trihybrid with potent cytotoxicity, might be applied as a promising skeleton for antitumor agents, which deserved further optimization.

[Effect of Silver Nanoparticles on Denitrification and Functional Gene Abundances of Sediment in Dagu River Estuary and Northwest of Jiaozhou Bay].

The influence of silver nanoparticles (AgNPs) on the denitrification performance, enzyme activity, and functional gene relative abundances of sediment was investigated based on the methods of laboratory simulation incubation in the Dagu River estuary and bay area in the northwest of Jiaozhou Bay. The different dosages of AgNPs (i.e., 0, 135, and 1350 mg·L-1 in final concentration) was added to the incubation system containing surface sediments and in-situ bottom water. During six days' incubation, the concentrations of NO3- and NO2-, NO3-, and NO2- reductases activity, and relative abundances of narG and nirS genes were measured to explore the effects of AgNPs on denitrification and its mechanism. The results showed that AgNPs significantly inhibited NO3- and NO2- reductive capacity, NO3- and NO2- reductase activity, and narG and nirS gene relative abundances, which led to aggravated accumulation of NO2-. The inhibition of NO2- reductase was significantly greater than that of NO3- reductase, and the inhibition of the nirS gene was significantly higher than that of the narG gene. The inhibition of NO3- reduction was mainly ascribed to the inhibition of functional genes, but the inhibition of NO2- reduction was mainly due to the inhibition of reductase activity. The inhibition of NO3- and NO2- reductive capacity, NO3- reductase activity, and narG and nirS gene relative abundances in the northwest of Jiaozhou Bay was significantly higher than that in the Dagu River estuary.